Nonracemic mixtures and uses thereof

ABSTRACT

Provided are compositions comprising unequal mixtures of (R)-amisulpride and (S)-amisulpride, or pharmaceutically acceptable salts thereof, where the amount of (R)-amisulpride is greater than the amount of (S)-amisulpride, compositions and medicaments comprising the same used for the treatment of various diseases and disorders, and methods of using same for the treatment of various diseases and disorders, including, but not limited to, dosage regimens. In addition, provided are various formulations thereof, including, but not limited to, formulations employing polymorphs of enantiomeric amisulpride.

FIELD OF THE INVENTION

The present inventions relate to pharmaceutical compositions ofnon-racemic amisulpride and methods and uses thereof.

BACKGROUND

Amisulpride is a member of the chemical class benzamide, and has thechemical name4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-ethylsulfonyl-2-methoxy-benzamide.The chemical structure of amisulpride is as follows:

There is a need for better treatments of psychiatric and mood disorders,including bipolar disorder and in particular depression associated withbipolar disorder. For example, psychiatrists indicate that about 25% ofpatients across all bipolar disorders are refractory during a manicepisode, while about 70% are refractory during a depressive episode.Thus, there is a need for drugs that remit depressive symptoms inbipolar patients.

Dopamine receptor antagonists are one class of drugs used to treatpsychiatric disorders, however efficacious D₂ occupancy levels are alsorelated to deleterious side effects. A need also therefore exists forcentral nervous system drugs (CNS) and in particular psychiatric drugsfor the treatment of depression and diseases and disorders with adepressive component, that provide a therapeutic effect with no orreduced side effects and in particular side effects associated withdopamine D₂ receptor occupancy.

Racemic amisulpride is sold under the tradename SOLIAN® as 400 mg tabletand as a solution for the treatment of acute and chronic schizophrenicdisorders, in which positive symptoms (such as delusions,hallucinations, thought disorders) and/or negative symptoms (such asblunted affect, emotional and social withdrawal) are prominent,including patients characterized by predominant negative symptoms, witha recommend total daily dose of 400-800 mg. However, movement relatedadverse events including tremor, rigidity, hypokinesia, hypersalivation,akathisia, dyskinesia are listed as “very common” in the label forracemic amisulpride in the 400-800 mg/day dosage range. Such asextrapyramidal symptoms are commonly associated with antipsychotic drugsemploying dopamine receptor blockade. Typically, extrapyramidal symptomsare observed at high dopamine receptor occupancy, e.g., at about 70-75%occupancy. Other side effects associated with racemic amisulprideinclude prolongation of the QT interval and increase in prolactin whichmay lead to galactorrhoea, amenorrhoea, gynaecomastia, breast pain,erectile dysfunction. Therefore, there is need for better psychiatricdrugs with reduced side effects.

A need exists for an amisulpride composition which has reduced adverseevents and a greater safety profile. A further need exists for anamisulpride composition which can effectively treat bipolar symptomsaccompanied with depression more effectively than current formulations.A still further need exists for an amisulpride formulation which isoptimized to antagonize the D₂ dopamine receptor associated with bipolarsymptoms and separately optimized to antagonize the 5-HT₇ serotoninreceptor associated with symptoms of depression.

SUMMARY

These and other objectives of the present invention make use of theunexpected discovery by the inventors that the R and S amisulprideisomers have different properties that were unexpected. The R isomer isa selective serotonin antagonist. In contrast the S isomer is a highlyselective D₂ dopamine antagonist. The present inventors provideamisulpride compositions tailored to provide specific antagonism effectsagainst the D₂ dopamine receptors and the 5-HT₇ receptors independent ofone another. In various aspects and embodiments, the amisulpridecompositions provide the ability to adjust the D₂ dopamine and 5-HT₇receptors antagonism activity and reduce the adverse effects associatedwith racemic amisulpride of comparable total dosage amounts. Adverseeffects associated with racemic amisulpride include, but are not limitedto, Extrapyramidal Symptoms (EPS), akathisia, sedation, metabolicparameters such as weight gain, glucose and lipids, prolactin relatedevents, sexual dysfunction and manic depression. In various aspects andembodiments, the degree of reduction is determined by the ratio of R toS amisulpride in the composition and total dosage amount.

The inventors of the present application have discovered that(R)-amisulpride is associated with serotonin 5-HT₇ receptors where theserotonergic activity of (R)-amisulpride has an antidepressant effect.Dopamine D2 antagonism resides primarily in the (S)-amisulpride and D2antagonism can help control the positive symptoms that may arise as aresult of treating depression. The inventors have discovered enrichmentof serotonin mood disorder benefits while minimizing D2 mediated sideeffects by using a non-racemic ratio of (R)-amisulpride and(S)-amisulpride to treat patients with bipolar disorder and inparticular depression associated with bipolar disorder. The inventorshave discovered that non-racemic ratios of R:S amisulpride can providesufficient 5-HT7 antagonist activity while reducing the level of D2antagonism to the level associated with antidepressant benefit, thusachieving serotonergic efficacy while limiting D2-associated undesirableside effects. Administration of a composition having a greater amount ofR than S amisulpride provides novel pharmacology which conferssignificant antidepressant benefits with reduced D2-related side effectsin patients with bipolar disorder.

It has been unexpectedly discovered that benefits can be obtained fromunequal mixtures of the (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, where the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride.It has been discovered that the serotonergic activity of(R)-(+)-amisulpride has an antidepressant effect. It has also beendiscovered that amisulpride enantiomers have differentstereoselectivities between dopamine D₂ and serotonin 5-HT₇ receptors,such that the relative potencies of mixtures of amisulpride enantiomerscan be changed to increase serotonin 5-HT7 potency relative to dopamineD2 receptor potency, and concomitantly provide efficacious compositions,methods of treatment, methods of receptor inhibition, and medicamentswhilst decreasing undesirable side effects associated with one or bothof the enantiomers.

It has been discovered that certain unequal mixtures of the(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, where the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride can provide an approachto the treatment of mood disorders, psychiatric disorders and/or mixedmood/psychotic disorders by increasing the proportion of 5-HT7antagonism provided by (R)-amisulpride in relation to D2 blockadeprovided by (S)-amisulpride in order to more effectively target mood andcognitive symptoms while still maintaining the anxiolytic andantipsychotic benefits of D2 blockade and concomitantly reducingdopamine-related extrapyramidal side effects.

The present inventors have demonstrated that the R-enantiomer is highlystereoselective for serotonin 5-HT7 receptors, such that the 5-HT7antagonism seen with amisulpride can be attributed almost exclusively tothe R-enantiomer. In addition, the present inventors have conductedpreclinical polysomnography (PSG) studies in rats that demonstrate rapideye movement (REM) suppression with R-amisulpride, with resultsconsistent with the effects reported for selective 5-HT7 antagonists.Also, the present inventors have shown in healthy human volunteers thatR-amisulpride demonstrates clinically meaningful and statisticallysignificant suppression of REM sleep, similar to what has been observedwith other 5-HT7 selective antagonists in human studies.

The present inventors have demonstrated that the S-enantiomer is highlystereoselective for dopamine D2 receptors with in vivo non-human primatePET imaging experiments. Also, the present inventors have shown inhealthy human volunteers that S-amisulpride demonstrates clinicallymeaningful dose-dependent D2 receptor occupancy.

In various aspects and embodiments, provided are various compositions,formulations, methods and medicaments comprising and/or employingunequal mixtures of the (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, where the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride,that can provide the discovered antidepressant activity of(R)-(+)-amisulpride while maintaining the mood stabilization activity of(S)-(−)-amisulpride and minimizing the undesirable side effectsassociated with higher levels of dopamine D2 receptor blockadeassociated with (S)-(−)-amisulpride.

It has been discovered by the inventors that, in various aspects andembodiments of the present inventions, a fixed-dose combination ofamisulpride enantiomers, defined in various embodiments by thecontribution of 5-HT₇ occupancy relative to D₂ occupancy exhibitsclinical benefit by allowing physicians to treat subjects with adominant 5-HT₇ pharmacodynamics while still maintaining adose-responsive underlying dopamine D₂ activity for a combined, and invarious embodiments improved, clinical benefit in depressive disorders.

Since the R and S isomer are separately prepared it is possible tocustomize formulations to provide the desired D₂ antagonism separatelyfrom the 5-HT7 antagonism by changing the ratio of the R and S isomersin the formulation. This customization is not possible with racemicamisulpride. The present inventions in various aspects and embodimentsallow for formulations which can avoid the problems traditionallyassociated with the racemic mixture.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1C present various analytical in vitro data for the inhibitionof radioligand binding activity by racemic amisulpride, (R)-amisulpride,and (S)-amisulpride, and various mixtures of (R)-amisulpride and(S)-amisulpride; where FIG. 1A presents data on the % inhibition ofdopamine D2 receptor binding; FIG. 1B presents data on the % inhibitionof serotonin 5-HT7 receptor binding; and FIG. 1C presents data onrelative receptor affinity (5-HT7: D2) for various mixtures of(R)-amisulpride and (S)-amisulpride.

FIG. 2 presents analytical data on the in vivo effects of(R)-amisulpride in a Rat Forced Swim Test, compared to vehicle andimipramine.

FIGS. 3A and 3B present analytical data on the in vivo effects of(R)-amisulpride on suppression of REM sleep time in rats; FIG. 3Apresenting data comparing vehicle to 10 mg/kg and 100 mg/kg of(R)-amisulpride, and FIG. 3B presenting data comparing vehicle to 10mg/kg, 30 mg/kg and 100 mg/kg of (R)-amisulpride.

FIGS. 3C, 3D, and 3E present analytical data on the in vivo effects of85:15 ratio (R:S-amisulpride) and racemic amisulpride (50:50R:S-amisulpride) on suppression of REM sleep time in rats. FIG. 3Cpresents data comparing vehicle to 30 mg/kg and 100 mg/kg of 85:15 ratio(R:S-amisulpride) and racemic amisulpride in REM sleep time (min). FIG.3D presents data comparing vehicle to 30 mg/kg and 100 mg/kg of 85:15ratio (R:S-amisulpride) and racemic amisulpride in NREM sleep time(min). FIG. 3E presents data comparing vehicle to 30 mg/kg and 100 mg/kgof 85:15 ratio (R:S-amisulpride) and racemic amisulpride in WAKE time(min).

FIG. 4 presents analytical data from human clinical studies on theeffects of (S)-amisulpride binding to dopamine D2 receptors in the brainof human volunteers using PET imaging.

FIG. 5 presents analytical data from human clinical studies on theeffects of (R)-amisulpride in suppressing REM sleep in human volunteersusing PSG to record sleep stages.

FIGS. 6A, 6B and 6C present analytical data on the effects of mixturesof amisulpride; where FIG. 6A presents data from human clinical studieson the binding to dopamine D2 receptors of an 85:15 ratio by weightpercentage (w/w %) of (R)-amisulpride to (S)-amisulpride, FIG. 6Billustrates data on a racemic (50:50 ratio by weight percentage mixtureof (R)-amisulpride to (S)-amisulpride), and FIG. 6C illustrates thesubstantial overlap of the 5-HT₇ effect with 30% to 50% D₂ receptoroccupancy that may be achieved with administration of an 85:15 ratio byweight percentage (w/w %) mixture of (R)-amisulpride to (S)-amisulpride.In FIG. 6B the mg designations within the field of the graph indicatethe amount of the indicted enantiomer in the racemic mixture. In FIG. 6Cthe grey shaded circles are the data for (S)-amisulpride from FIG. 6Bplotted on the FIG. 6C x-axis as the total mg amount required to deliverthe indicated amount of (S)-amisulpride in the(R)-amisulpride:(S)-amisulpride (85:15) mixture, the dark shaded circlesare the data for (R)-amisulpride from FIG. 6B plotted on the FIG. 6Cx-axis as the total mg amount required to deliver the indicated amountof (R)-amisulpride in the (R)-amisulpride:(S)-amisulpride (85:15)mixture, and the white diamond symbols are data for administration of an85:15 ratio by weight percentage (w/w %) mixture of (R)-amisulpride to(S)-amisulpride.

FIGS. 7A-7C present various analytical data and images for Form Acrystals of (R)-amisulpride, where FIG. 7A presents a DSC thermogram;FIG. 7B a XRPD pattern; and FIG. 7C a micrograph image.

FIGS. 8A-8D present various analytical data and images for Form A′crystals of (S)-amisulpride, where FIG. 8A presents a DSC thermogram;FIG. 8B a XRPD pattern; FIG. 8C a micrograph image; and FIG. 8D a DVSwater sorption isotherm.

FIG. 9 is an NMR spectrum of anR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidefreebase of crystal Form A.

FIG. 10 is an NMR spectrum of anS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidefreebase of crystal Form A′.

FIG. 11A is an NMR spectrum of anR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidefreebase of crystal Form A, and FIG. 11B illustrates the number sequenceused for the assignment of peaks in FIG. 11A.

FIG. 12A is an ¹³C NMR spectrum of anR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidefreebase of crystal Form A, and FIG. 12B illustrates the number schemeused for the assignment of peaks in FIG. 12A.

FIG. 13A is an NMR spectrum of anS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidefreebase of crystal Form A′, and FIG. 13B illustrates the numbersequence used for the assignment of peaks in FIG. 13A.

FIG. 14A is an ¹³C NMR spectrum of anS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidefreebase of crystal Form A′, and FIG. 14B illustrates the number schemeused for the assignment of peaks in FIG. 14A.

FIGS. 15A, 15B, and 15C present analytical data on the effects ofmixtures of amisulpride.

FIG. 15A presents data from human clinical studies on the effects of(R)-amisulpride (dark circles) on 5-HT₇ shown by suppression of REMsleep from Example 5, where the x-axis in the top graph is 50:50 racemicamisulpride, and the x-axis in the bottom graph is 85:15 ratio by weightpercentage (w/w %) of R:S-amisulpride.

FIG. 15B presents data from human clinical studies on the binding todopamine D2 receptors of (S)-amisulpride and an 85:15 ratio by weightpercentage (w/w %) of (R)-amisulpride to (S)-amisulpride. The x-axis inthe top graph is 50:50 racemic amisulpride. The top graph shows theamount of (S)-amisulpride (grey circles) has on D2 occupancy based ondata from Example 4. The x-axis in the bottom graph is 85:15 ratio of(R)-amisulpride to (S)-amisulpride, showing the amount of(S)-amisulpride (grey circles) and 85:15 ratio (white diamonds) have onD2 occupancy based on data from Example 4 and Example 6, respectively.

FIG. 15C illustrates the substantial overlap of the 5-HT₇ effect with30% to 50% D₂ receptor occupancy that may be achieved withadministration of an 85:15 ratio by weight percentage (w/w %) mixture of(R)-amisulpride to (S)-amisulpride. The x-axis in the top graph is thetotal amount of racemic amisulpride. The mg designations indicate theamount of the indicted enantiomer in the racemic mixture. The greyshaded circles are the data for (S)-amisulpride from Example 4, showingthe effect of (S)-amisulpride has on D2 occupancy. The dark circles arethe data for (R)-amisulpride from Example 5, showing the effect of(R)-amisulpride has on 5-HT₇. The x-axis in the bottom graph is thetotal amount of 85:15 ratio R:S amisulpride. The mg designationsindicate the amount of the indicted enantiomer in the 85:15 ratiomixture. The grey shaded circles are the data for (S)-amisulpride fromExample 4, showing the effect of (S)-amisulpride has on D2 occupancy.The dark circles are the data for (R)-amisulpride from Example 5,showing the effect of (R)-amisulpride has on 5-HT₇. The white diamondsare data for the 85:15 ratio R:S amisulpride from Example 6 (D2occupancy).

FIG. 16 presents a calculated XRPD based on single crystal structuredetermination for (R)-amisulpride Form A.

FIG. 17 presents a calculated XRPD based on single crystal structuredetermination for (S)-amisulpride Form A′.

DETAILED DESCRIPTION

The present inventions relate to pharmaceutical compositions comprisingunequal mixtures of amisulpride enantiomers, medicaments for thetreatment of a disorder comprising unequal mixtures of amisulprideenantiomers, methods of treating a disorder in a subject with apharmaceutical compositions comprising unequal mixtures of amisulprideenantiomers, methods of inhibiting dopamine D₂ activity and serotonin5-HT7 activity in a subject with a pharmaceutical compositionscomprising unequal mixtures of amisulpride enantiomers.

In various aspects, the disorder which the medicaments and methods ofthe present inventions treat comprise one or more of a: psychiatricdisorder; mood disorder; depressive disorder; as an adjunctive treatmentof major depressive disorder; bipolar disorder; bipolar depression;schizophrenia; negative symptoms of schizophrenia; treatment resistantdepression (TRD); schizoaffective disorder; anxiety disorder;obsessive-compulsive disorder; behavior disturbances associated with aneurocognitive disorder; conduct disorder; neurological disorder;medication-induced movement disorder; and motor disorder.

Amisulpride has a single asymmetric center and as a result exists in twoenantiomeric forms:R-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(also referred to as:(R)-(+)-4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide,and under the IUPAC name as4-amino-5-(ethanesulfonyl)-N-{[(2R)-1-ethylpyrrolidin-2-yl]methyl}-2-methoxybenzamide),abbreviated herein as (R)-(+)-amisulpride or (R)-amisulpride; andS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(also referred to as:(S)-(−)-4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide,and under the IUPAC name as4-amino-5-(ethanesulfonyl)-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-2-methoxybenzamide),abbreviated herein as (S)-(−)-amisulpride or (S)-amisulpride. These twoenantiomeric forms have the following chemical structures:

R-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide,(R)-amisulpride

S-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(S)-amisulpride

Dopamine D₂-related side effects are well-known from clinicalexperience, it has been observed that the incidence of extrapyramidalside effects increases when occupancy exceeds the 80% threshold andstudies have shown that extrapyramidal side effects occur even at about70-75% occupancy (G. Grunder, et al., Nature, 8, 198-202, (2009);Nyberg, et al., Am. J. Psychiatry, 156, 873-875 (1999); Farde, et al.Arch. Gen. Psychiatry, 49, 538-544 (1992)). However, it is believed thatvery high D2/3 receptor occupancy is not only associated with butgenerally required for effectiveness against the positive symptoms ofschizophrenia and that the antipsychotic effects of dopamine receptorantagonists occur within a therapeutic window between 60 and 80%striatal D2/3 receptor occupancy. (G. Grunder, et al., Nature, 8,198-202, (2009)).

Dopamine D₂-related side effects are also known from clinical experiencewith racemic amisulpride and include Extrapyramidal Symptoms (EPS),Tardive Dyskinesia (TD), and Akathisia. (C. Coulouvrat et al.,International Clinical Psychopharmacology, Vol 14, No. 4, 209-218(1999)). It has been determined that in general D₂ occupancy greaterthan about 67% results in side-effects that limit the ability of theunderlying 5-HT₇ pharmacodynamics to contribute to clinical benefit as afunction of dose. (Farde, et al. Arch. Gen. Psychiatry, 49, 538-544(1992). The impact of D₂ occupancy is associated with age with EPSevents being noted in older patients with Alzheimer's at occupancies ofabout 60%; clinically meaningful responses were seen at occupancies of43%. (Reeves et al., Brain, 140, 1117-1127). Similar results were alsoobtained with older patients in general. (Uchida et al., The American J.of Geriatic Pyschiatry, 22 (1) 1007-1016).

Selective serotonin 5-HT7 antagonists are known to modulate rapid eyemovement (REM) sleep in rodents and humans (Bonaventure et al, 2012). Ingeneral, REM suppression is understood to be a translational biomarkerof serotonergic antidepressant-like activity appropriate for selectinghuman doses. The 5-HT7 receptor has been shown, through variouspharmacological tools (receptor-specific agonists and antagonists) andthrough the use of knockout models, to be involved in the centralregulation of sleep and circadian rhythms, mood, and cognition. Thesesame three domains are often critically impaired in mood disorders suchas major depressive disorder and bipolar disorder, as well as inpsychotic disorders.

In the course of several experiments, the present inventors haveunexpectedly discovered that a benefit can be obtained from unequalmixtures of the (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, where the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride.It has been discovered that the serotonergic activity of(R)-(+)-amisulpride has an antidepressant effect. It has also beendiscovered that amisulpride enantiomers have differentstereoselectivities between dopamine D₂ and serotonin 5-HT₇ receptors,such that the relative potencies of mixtures of amisulpride enantiomerscan be changed to increase serotonin 5-HT7 potency relative to dopamineD2 receptor potency, and concomitantly provide efficacious compositions,methods of treatment, methods of receptor inhibition, and medicamentswhilst decreasing undesirable side effects associated with one or moreof the enantiomers.

It has been discovered that certain unequal mixtures of the(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, where the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride can provide an approachto the treatment of mood disorders, psychiatric disorders and/or mixedmood/psychotic disorders by increasing the proportion of 5-HT7antagonism provided by (R)-amisulpride in relation to D2 blockadeprovided by (S)-amisulpride in order to more effectively target mood andcognitive symptoms while still maintaining the anxiolytic andantipsychotic benefits of D2 blockade whilst concomitantly reducingdopamine-related extrapyramidal side effects.

The present inventors have demonstrated that the R-enantiomer is highlystereoselective for serotonin 5-HT7 receptors, such that the 5-HT7antagonism seen with amisulpride can be attributed almost exclusively tothe R-enantiomer. In addition, the present inventors have conductedpreclinical polysomnography (PSG) studies in rats that demonstrate REMsuppression with R-amisulpride, with results consistent with the effectsreported for selective 5-HT7 antagonists. Also, the present inventorshave shown in healthy human volunteers that R-amisulpride demonstratesclinically meaningful and statistically significant suppression of REMsleep, similar to what has been observed with other 5-HT7 selectiveantagonists in human studies.

The present inventors have demonstrated that the S-enantiomer is highlystereoselective for dopamine D2 receptors with in vivo non-human primatePET imaging experiments. Also, the present inventors have shown inhealthy human volunteers that S-amisulpride demonstrates clinicallymeaningful dose-dependent D2 receptor occupancy.

In various aspects and embodiments, provided are various compositions,formulations, methods and medicaments comprising and/or employingunequal mixtures of the (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, where the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride,that can provide the discovered antidepressant activity of(R)-(+)-amisulpride while maintaining the mood stabilization activity of(S)-(−)-amisulpride while minimizing the undesirable side effectsassociated with higher levels of dopamine D2 receptor blockadeassociated with (S)-(−)-amisulpride.

It has been discovered by the inventors that, in various aspects andembodiments of the present inventions, a fixed-dose combination ofamisulpride enantiomers, defined in various embodiments by thecontribution of 5-HT₇ occupancy relative to D₂ occupancy exhibitsclinical benefit by allowing physicians to treat subjects with adominant 5-HT₇ pharmacodynamics while still maintaining adose-responsive underlying dopamine D₂ activity for a combined, and invarious embodiments improved, clinical benefit in depressive disorders.

The present compositions comprise an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, where the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride, and the ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, is in a ratio effective to provide in asubject after administration: an occupancy of dopamine D2 receptorsbetween about 20% and about 60%; and a suppression of time in rapid eyemovement (REM) sleep is characterized, for example, by one or more of:(a) a decrease in REM sleep by an amount greater than about 10 minutes;(b) a latency to REM sleep by an amount greater than about 20 minutes,or (c) a decrease in total REM sleep time relative to total sleep timeby an amount greater than about 5%. In various embodiments, the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about50 mg and about 1000 mg, in various embodiments between about 200 mg andabout 700 mg, and in various embodiments between about 350 mg and about700 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 800 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 100 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 200 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about300 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 500 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg.

The relative amounts of R and S amisulpride in the composition arechosen such that the D₂ occupancy is about 20% to about 60%. Occupanciesabove about 65% are associated with adverse events. Considering adverseevents, in some embodiments, the amount of S isomer in the compositionshould not exceed the amount necessary to achieve about 60% or about 50%D₂ occupancy. In some embodiments, the minimum S isomer should besufficient to achieve about 20% to about 25% D₂ occupancy. In someembodiments, the minimum S isomer is sufficient to achieve about 30% D₂occupancy.

The amount R-amisulpride administered should be sufficient to achieve areduction on the time a patient spends in REM sleep time of at leastabout 10 minutes to about 45 minutes, about 15 minutes to 30 minutes, orabout 18 minutes to about 31 minutes.

In some embodiments, the relative ratios of R:S isomers in anamisulpride composition is about 63:37 to about 95:5 by weight of freebase. In some embodiments, the ratio of R:S is about 77:23 to about 93:7by weight of free base. In some embodiments, the ratio of R:S is about74:26 to about 92:8 by weight of free base. In some embodiments, theratio of R:S is about 65:35 to about 88:12 by weight of free base. Insome embodiments, the ratio of R:S is about 75:25 to about 88:12 byweight of free base. In some embodiments, the ratio of R:S is about80:20 to about 88:12 by weight of free base. In some embodiments, theratio of R:S is about 80:20 to about 90:10 by weight of free base. Invarious embodiments the ratio of R:S is about 85:15 by weight of freebase.

In various aspects, the compositions of the present inventions comprisean unequal mixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, where the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride,and the ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, is in a ratio effective toprovide in a subject after administration inhibition of dopamine D2activity and serotonin 5-HT7 activity in said subject such that theratio of the serotonin 5-HT7 receptor inhibitory constant to thedopamine D2 receptor inhibitory constant is in the range between about 2to about 6. In various embodiments, the ratio of the serotonin 5-HT7receptor inhibitory constant to the dopamine D2 receptor inhibitoryconstant is in the range between about 3 to about 5; and in variousembodiments, the ratio of the serotonin 5-HT7 receptor inhibitoryconstant to the dopamine D2 receptor inhibitory constant is about 4. Invarious embodiments, the dopamine D2 receptor inhibitory constant is inthe range between about 11 nM to about 20 nM and the serotonin 5-HT7receptor inhibitory constant is in a range between about 40 nM to about85 nM. In various embodiments, the dopamine D2 receptor inhibitoryconstant is in the range between about 15 nM to about 20 nM and theserotonin 5-HT7 receptor inhibitory constant is in a range between about50 nM to about 80 nM. In various embodiments, the dopamine D2 receptorinhibitory constant is about 17 nM and the serotonin 5-HT7 receptorinhibitory constant is about 66 nM. In various embodiments, the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about50 mg and about 1000 mg, in various embodiments between about 200 mg andabout 700 mg, and in various embodiments preferably between about 350 mgand about 700 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 800 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 100 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 200 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about300 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 500 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg. In variousembodiments, such compositions comprise a ratio of (R)-(+)-amisulprideto (S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,that is in the range between about 80:20 to about 90:10 by weight offree base; and preferably in various embodiments the ratio is about85:15 by weight of free base.

In various aspects, the compositions of the present inventions comprisea ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, that is in the range betweenabout 80:20 to about 90:10 by weight of free base. In variousembodiments, the compositions comprise a ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, thatis about 85:15 by weight of free base. In various embodiments, thecompositions comprise a ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, thatis in the range between about 63:37 to about 95:5 by weight of freebase. In various embodiments, the compositions comprise a ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, that is in the range between about 77:23 toabout 93:7 by weight of free base. In various embodiments, thecompositions comprise a ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, thatis in the range between about 74:26 to about 92:8 by weight of freebase. In various embodiments, the compositions comprise a ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, that is in the range between about 65:35 toabout 88:12 by weight of free base. In various embodiments, thecompositions comprise a ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, thatis in the range between about 75:25 to about 88:12 by weight of freebase. In various embodiments, the compositions comprise a ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, that is in the range between about 80:20 toabout 88:12 by weight of free base. In various embodiments, thecompositions comprise a ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, thatis in the range between about 80:20 to about 90:10 by weight of freebase.

In various embodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 50 mg and about 1000 mg, in variousembodiments between about 200 mg and about 700 mg, and in variousembodiments preferably between about 350 mg and about 700 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 100 mg and about 800 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 100 mg and about 600 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 100 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about200 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 300 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 400 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about500 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 700 mg.

It is to be understood that when an amisulpride enantiomer is said to bepresent in a certain weight amount, and such enantiomeric amisulpride isprovided as a pharmaceutically acceptable salt thereof, that the weightamount refers to the amisulpride enantiomer portion exclusive of thesalt portion, that is as the free base. Accordingly, it is to beunderstood that when a weight ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride is recited, it is the weight ratios only of theamisulpride portions exclusive of any salt portion especially if onlyone of the amisulpride enantiomers is present as a pharmaceuticallyacceptable salt thereof or the amisulpride enantiomers are present asdifferent pharmaceutically acceptable salts.

It is to be understood, that in various aspects, the present inventionsprovide compositions comprising unequal mixtures of amisulprideenantiomers (or a pharmaceutically acceptable salt of one or more of theenantiomers) and one or more pharmaceutically acceptable excipient,carrier, adjuvant, or vehicle. In various embodiments, a composition ofthe present inventions is formulated for administration to a subject inneed of such composition. In various embodiments, a composition of theinventions is formulated for oral administration to a subject; and thatin various embodiments the compositions are provided in a solid oraldosage form.

In various embodiments, wherein the compositions comprising unequalmixtures of amisulpride enantiomers (or a pharmaceutically acceptablesalt of one or more of the enantiomers) and one or more pharmaceuticallyacceptable excipient, carrier, adjuvant, or vehicle, the combined amountof (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 50 mgand about 1000 mg, in various embodiments between about 200 mg and about700 mg, and in various embodiments preferably between about 350 mg andabout 700 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 800 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 100 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 200 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about300 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 500 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg. In variousembodiments, such compositions comprise a ratio of (R)-(+)-amisulprideto (S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,that is in the range between about 80:20 to about 90:10 by weight; andin various embodiments the ratio is about 85:15 by weight.

Dosing of (S)-(−)-amisulpride should be sufficient to achieve a D₂occupancy level of between about 20% and about 60% to achieve thedesired therapeutic effect with reduced adverse events. At levels aboveabout 70% to about 75% the adverse events occur at an increasingfrequency and severity. Higher dosing levels to achieve a greater D₂occupancy can be used if the patient does not experience an unacceptablelevel of adverse events. Typical daily doses of (S)-(−)-amisulpride arefrom about 5 mg to about 150 mg, about 10 mg to about 150 mg, or about15 mg to about 100 mg. All doses are as the free base.

Typical daily doses of (R)-(+)-amisulpride free base are from about 50mg to about 1000 mg, preferably from about 100 mg to about 600 mg, stillmore preferably from 150 mg to about 600 mg, yet another preferred dailydose is from 170 mg to about 340 mg. The doses may be administered in asingle daily dose or in divided doses.

If the (R)-(+)-amisulpride and (S)-(−)-amisulpride are combined into asingle dosage form, the relative amounts of each should be about77:23-93:7 by weight of free base as the free base, from about 80:20 toabout 90:10, or about 85:15. The ratio of (R)-(+)-amisulpride and(S)-(−)-amisulpride may be determined by the relative amounts of eachnecessary to achieve the desired therapeutic effect.

In various aspects, the present inventions provide medicaments for andprovide methods of treating one or more of a neurological disorder and apsychiatric disorder in a subject, comprising administering apharmaceutical composition comprising an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, wherein the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride.

To aid in conciseness of explanation, the term “R dominant amisulpridemixture” shall be used to mean: an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, wherein the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride.

In various aspects, the present inventions provide a method of treatinga psychiatric disorder in a subject comprising administering acomposition comprising a R dominant amisulpride mixture where themixture is administered in a therapeutically effective amount to providein a subject after administration: an occupancy of dopamine D2 receptorsbetween about 20% and about 60%; and a suppression of time in rapid eyemovement (REM) sleep is characterized, for example, by one or more of:(a) a decrease in REM sleep by an amount greater than about 10 minutes;(b) a latency to REM sleep by an amount greater than about 20 minutes,or (c) a decrease in total REM sleep time relative to total sleep timeby an amount greater than about 5%. In various embodiments, suchcompositions comprise a ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, thatis in the range between about 80:20 to about 90:10 by weight; andpreferably in various embodiments the ratio is about 85:15 by weight. Invarious embodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 50 mg and about 1000 mg, in variousembodiments between about 200 mg and about 700 mg, and in variousembodiments preferably between about 350 mg and about 700 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 100 mg and about 800 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 100 mg and about 600 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 100 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about200 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 300 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 400 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about500 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 700 mg.

In various aspects, the present inventions provide a method of treatinga psychiatric disorder in a subject comprising administering acomposition comprising a R dominant amisulpride mixture where themixture is administered in a therapeutically effective amount to providein a subject after administration: inhibition of dopamine D2 activityand serotonin 5-HT7 activity in said subject such that the ratio of theserotonin 5-HT7 receptor inhibitory constant to the dopamine D2 receptorinhibitory constant is in the range between about 2 to about 6. Invarious embodiments, the ratio of the serotonin 5-HT7 receptorinhibitory constant to the dopamine D2 receptor inhibitory constant isin the range between about 3 to about 5; and in various embodiments, theratio of the serotonin 5-HT7 receptor inhibitory constant to thedopamine D2 receptor inhibitory constant is about 4. In variousembodiments, the dopamine D2 receptor inhibitory constant is in therange between about 11 nM to about 20 nM and the serotonin 5-HT7receptor inhibitory constant is in a range between about 40 nM to about85 nM. In various embodiments, the dopamine D2 receptor inhibitoryconstant is in the range between about 15 nM to about 20 nM and theserotonin 5-HT7 receptor inhibitory constant is in a range between about50 nM to about 80 nM. In various embodiments, the dopamine D2 receptorinhibitory constant is about 17 nM and the serotonin 5-HT7 receptorinhibitory constant is about 66 nM. In various embodiments, suchcompositions comprise a ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, thatis in the range between about 80:20 to about 90:10 by weight; andpreferably in various embodiments the ratio is about 85:15 by weight. Invarious embodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 50 mg and about 1000 mg, in variousembodiments between about 200 mg and about 700 mg, and in variousembodiments preferably between about 350 mg and about 700 mg.

In various aspects, the present inventions provide a method of treatinga psychiatric disorder in a subject comprising administering apharmaceutical composition comprising one or more pharmaceuticallyexcipient, carrier, adjuvant, or vehicle, and a combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride between about 50 mg andabout 1000 mg, in various embodiments between about 200 mg and about 700mg, and in various embodiments preferably between about 350 mg and about700 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 800 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 100 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 200 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about300 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 500 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg. In variousembodiments, such composition comprises a ratio of (R)-(+)-amisulprideto (S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,that is in the range between about 80:20 to about 90:10 by weight; andpreferably in various embodiments the ratio is about 85:15 by weight.

In various aspects, the present inventions provide medicaments for andprovide methods of treating a psychiatric disorder in a human subject,comprising administering on a treatment cycle an amount of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, andan amount of (S)-(−)-amisulpride, or a pharmaceutically acceptable saltthereof, in a combined amount between about 50 mg and about 1000 mg, invarious embodiments between about 200 mg and about 700 mg, and invarious embodiments preferably between about 350 mg and about 700 mg pertreatment cycle to a human subject in need thereof, wherein the amountof (R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulprideduring the treatment cycle. In various embodiments, the combined amountof (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mgand about 800 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 100 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 200 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about300 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 500 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg. In variousembodiments, the enantiomeric ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride over a treatment cycle of the combined amount is inthe range between about 80:20 to about 90:10 by weight; and preferablyin various embodiments the ratio is about 85:15 by weight. In variousembodiments, the (R)-amisulpride, or a pharmaceutically acceptable saltthereof, and the (S)-amisulpride, or a pharmaceutically acceptable saltthereof, are given separately during a treatment cycle. In variousembodiments, the enantiomeric ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride over a treatment cycle is about 85:15 by weight, thetreatment cycle is daily and the total amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 200 mg over the treatment cycle. In variousembodiments, the enantiomeric ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride over a treatment cycle is about 85:15 by weight, thetreatment cycle is daily and the total amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 400 mg over the treatment cycle. In variousembodiments, of the aspects and embodiments of treating a psychiatricdisorder in a subject, or both a neurological disorder and a psychiatricdisorder, the disorder is one or more of a mood disorder, bipolardisorder (BPD), depression, bipolar depression, major depressivedisorder (MDD), as an adjunctive treatment of major depressive disorder,major depressive disorder with mixed features (MDD-MF), treatmentresistant depression (TRD), schizophrenia, negative symptoms ofschizophrenia, and schizoaffective disorder. In various embodiments, theprovided are medicaments and methods for treatment of major depressiveepisodes associated with bipolar I disorder.

In various aspects, the present inventions provide medicaments for andprovide methods of inhibiting dopamine D2 activity and serotonin 5-HT7activity in a subject comprising administering to a subject an effectiveamount of an unequal mixture of (R)-(+)-amisulpride, or apharmaceutically acceptable salt thereof, and (S)-(−)-amisulpride, or apharmaceutically acceptable salt thereof. In various embodiments, theinhibition of dopamine D2 activity and the inhibition serotonin 5-HT7activity comprises: an occupancy of dopamine D2 receptors between about20% and about 60%; and a suppression of the time in rapid eye movement(REM) sleep as characterized by one or more of: (a) a decrease in REMsleep by an amount greater than about 10 minutes, (b) a latency to REMsleep by an amount greater than about 20 minutes, or (c) a decrease intotal REM sleep time relative to total sleep time by an amount greaterthan about 5%.

In various embodiments of the methods of inhibiting dopamine D2 activityand serotonin 5-HT7 activity in a subject, the unequal mixture of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, and(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof,comprises an amount of (R)-(+)-amisulpride that is greater than theamount of (S)-(−)-amisulpride, and in various embodiments, the ratio of(R)-amisulpride to (S)-amisulpride, or pharmaceutically acceptable saltsthereof, is in the range between about 80:20 to about 90:10 by weight;and preferably in various embodiments the ratio is about 85:15 byweight.

In various embodiments of the methods of inhibiting dopamine D2 activityand serotonin 5-HT7 activity in a subject, the unequal mixture of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, and(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof, theof (R)-amisulpride, or a pharmaceutically acceptable salt thereof, and(S)-amisulpride, or a pharmaceutically acceptable salt thereof, in arepresent in a combined amount between about 50 mg and about 1000 mg andthe amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride. In various embodiments, the ratio of(R)-amisulpride to (S)-amisulpride, or pharmaceutically acceptable saltsthereof, is in the range between about 80:20 to about 90:10 by weight;and preferably in various embodiments the ratio is about 85:15 byweight.

In various embodiments of the methods of inhibiting dopamine D2 activityand serotonin 5-HT7 activity in a subject, the unequal mixture of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, and(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof, theof (R)-amisulpride, or a pharmaceutically acceptable salt thereof, and(S)-amisulpride, or a pharmaceutically acceptable salt thereof, in arepresent in a combined amount between about 50 mg and about 1000 mg, invarious embodiments between about 200 mg and about 700 mg; and invarious embodiments the combined amount is preferably between about 350mg and about 700 mg; and the amount of (R)-(+)-amisulpride is greaterthan the amount of (S)-(−)-amisulpride. In various embodiments, theratio of (R)-amisulpride to (S)-amisulpride, or pharmaceuticallyacceptable salts thereof, is in the range between about 80:20 to about90:10 by weight; and preferably in various embodiments the ratio isabout 85:15 by weight. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 800 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 100 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 200 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about300 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 500 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg.

In various embodiments of the methods of inhibiting dopamine D2 activityand serotonin 5-HT7 activity in a subject, the inhibition takes place ina subject suffering from one or more psychiatric disorders, aneurological disorder or a combination thereof. In various embodiments,the disorder is one or more of a mood disorder, bipolar disorder (BPD),depression, bipolar depression, major depressive episodes associatedwith bipolar I disorder, major depressive disorder (MDD), as anadjunctive treatment of major depressive disorder, major depressivedisorder with mixed features (MDD-MF), treatment resistant depression(TRD), schizophrenia, negative symptoms of schizophrenia, andschizoaffective disorder.

In various embodiments of the methods of inhibiting dopamine D2 activityand serotonin 5-HT7 activity in a subject, the inhibition takes place ina subject suffering from one or more psychiatric disorders, the unequalmixture of (R)-(+)-amisulpride, or a salt thereof, and(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof ispresent in a therapeutically effective amount. In various embodiments ofthe methods of inhibiting dopamine D2 activity and serotonin 5-HT7activity in a subject, the inhibition takes place in a subject sufferingfrom one or more psychiatric disorders, the unequal mixture of(R)-(+)-amisulpride, or a salt thereof, and (S)-(−)-amisulpride, or apharmaceutically acceptable salt thereof is administered to said subjectin a therapeutically effective amount.

It is to be understood, that in various aspects and embodiments of thevarious compositions, formulations, methods and medicaments of thepresent inventions, the compositions comprising unequal mixtures ofamisulpride enantiomers (or a pharmaceutically acceptable salt of one ormore of the enantiomers) further comprise one or more pharmaceuticallyacceptable excipient, carrier, adjuvant, or vehicle. In variousembodiments, such compositions are formulated for formulated for oraladministration to a subject; and that in various embodiments thecompositions are provided in an oral dosage form. In variousembodiments, the oral dosage form is in the form of a powder, tablet,caplet, capsule, oral solution, or oral suspension. In variousembodiments, the oral dosage form is a solid oral dosage form. Invarious embodiments the solid oral dosage form comprises a tablet, andin various embodiments the solid oral dosage form comprises a capsule.

It is to be understood, that in various embodiments that one or both ofthe enantiomeric amisulprides used in the various compositions,formulations, methods and medicaments of the present inventions is acrystalline form of the free base of the enantiomeric amisulpride ofcrystalline Forms A and Form A′ as described in FIGS. 7 A-C and 8 A-D.In various embodiments, the (R)-(+)-amisulpride is crystalline(R)-(+)-amisulpride of crystal Form A; the (S)-(−)-amisulpride iscrystalline (S)-(−)-amisulpride of crystal Form A′, or both. In variousembodiments, the (R)-(+)-amisulpride is crystalline (R)-(+)-amisulprideof crystal Form A and has greater than about 95% chemical purity; the(S)-(−)-amisulpride is crystalline (S)-(−)-amisulpride of crystal FormA′ and has greater than about 95% chemical purity, or the(R)-(+)-amisulpride is crystalline (R)-(+)-amisulpride of crystal Form Ahaving a greater than about 95% chemical purity and the(S)-(−)-amisulpride is crystalline (S)-(−)-amisulpride of crystal FormA′ having greater than about 95% chemical purity.

In various embodiments, crystalline forms of the present inventions haveseveral advantageous physical properties. For example, in contrast to(S)-amisulpride D-tartrate crystalline forms, the (R)-amisulpride Form Aand (S)-amisulpride Form A′ crystalline forms are substantiallynon-hygroscopic, exhibiting less than a 0.5% maximum mass change inwater sorption isotherms, at 25° C. scanned over 0 to 95% relativehumidity, as measured by dynamic vapor sorption (DVS), whereascrystalline (S)-amisulpride D-tartrate was found to be highlyhygroscopic, exhibiting a 52±9% (n=4, σ=18.25) maximum mass change inwater sorption isotherms, at 25° C. scanned over 0 to 95% relativehumidity, as measured by DVS.

The abbreviation “DSC” refers to differential scanning calorimetry; theabbreviation XRPD refers to x-ray powder diffraction, the abbreviationNMR refers to nuclear magnetic resonance, the abbreviation DVS refersto, dynamic vapor sorption, the abbreviation HPLC refers to highperformance liquid chromatography, and the abbreviation GC refers to gaschromatography. The abbreviations (R)-(+)-amisulpride and(R)-amisulpride refer toR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide.The abbreviations (S)-(−)-amisulpride and (S)-amisulpride refer toS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide.Other abbreviations not explicitly described herein have their normalmeanings in the art.

These and other objects, features, and advantages of the inventions willbecome apparent from the following detailed description of the variousaspects and embodiments of the inventions taken in conjunction with theaccompanying tables and drawings.

All published documents cited herein are hereby incorporated herein byreference in their entirety.

To facilitate the understanding of the present inventions, the followingdefinitions are provided. It is to be understood that, in general, termsnot otherwise defined are to be given their meaning or meanings asgenerally accepted in the art. The terminology used herein is for thepurpose of describing particular embodiments only and is not intended tolimit the scope of the present inventions which will be limited only bythe appended claims.

Reference in the specification to “one embodiment,” “an embodiment,”“one aspect,” or “an aspect” means that a particular, feature, structureor characteristic described in connection with the embodiment or aspectis included in at least one embodiment or aspect of the teachings.

As used herein, the recitation of“amisulpride,” unless expressly furtherlimited, includes pharmaceutically acceptable salts of amisulpride. Asused herein, the term “racemic amisulpride” refers to a 50:50 mixture byweight of (R)-amisulpride and (S)-amisulpride.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptablesalts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Although pharmaceutically acceptable counter ions will bepreferred for preparing pharmaceutical formulations, other anions arequite acceptable as synthetic intermediates. Thus X may bepharmaceutically undesirable anions, such as iodide, oxalate,trifluoromethanesulfonate and the like, when such salts are chemicalintermediates.

In various aspects, the present inventions provide a compositionscomprising unequal mixtures of amisulpride enantiomers (or apharmaceutically acceptable salt of one or more of the enantiomers) andone or more pharmaceutically acceptable excipient, carrier, adjuvant, orvehicle. In various embodiments, a composition of the present inventionsis formulated for administration to a subject in need of suchcomposition. In various embodiments, a composition of the inventions isformulated for oral administration to a subject.

As used herein, the term “subject,” to which administration iscontemplated includes, but is not limited to, humans (i.e., a male orfemale of any age group, e.g., a pediatric subject (e.g., infant, child,adolescent) or adult subject (e.g., young adult, middle-aged adult orsenior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesusmonkeys); mammals, including commercially relevant mammals such ascattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds,including commercially relevant birds such as chickens, ducks, geese,quail, and/or turkeys.

Compositions of the present inventions may be administered orally,parenterally, by inhalation, topically, rectally, nasally, buccally,sublingually, vaginally or via an implanted reservoir. The term“parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques. Preferably, the compositions are administeredorally, intraperitoneally or intravenously. Sterile injectable forms ofthe compositions of the present inventions may be aqueous or oleaginoussuspension. These suspensions may be formulated according to techniquesknown in the art using suitable dispersing or wetting agents andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, such as, for example, as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed, include but are not limited to, water, Ringer's solution andisotonic sodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium.Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including capsules,tablets, aqueous suspensions or solutions.

Unless otherwise specified, the word “includes” (or any variationthereon, e.g., “include”, “including”, etc.) is intended to beopen-ended. For example, “A includes 1, 2 and 3” means that A includesbut is not limited to 1, 2 and 3.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In various embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a subject prior to the onset ofsymptoms (e.g., in light of a history of symptoms and/or in light ofgenetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

As used herein, the phrase “on a free base basis” indicates that theamount of amisulpride (R and S-amisulpride) is measured based on themolecular weight of amisulpride free base. Unless specified otherwise,the weight amount described herein for amisulpride (e.g., racemic, R, S,or unequal mixtures of amisulpride) refers to the free base. Forexample, in a mixture of 85:15 ratio of R:S-amisulpride by weight, theamount of amisulpride is measured based on the molecular weight of R andS-amisulpride free base unless stated otherwise. In some embodiments,when referring to the combined amount of (R)-amisulpride and(S)-amisulpride, e.g., between about 50 mg and about 1000 mg, the amountis based on the weight of the free base unless specified otherwise.

The compounds disclosed herein can include isotopes. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. In someembodiments, one or more atoms of the compounds can be replaced orsubstituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, one or more hydrogen atoms in a compoundof the present disclosure can be replaced or substituted by deuterium.

As used herein, and unless otherwise specified, the term “about”, whenused in connection with a numeric value or range of values may vary by5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or0.1% of the recited value or range of values. In some embodiments, thenumeric value or range of values vary by 5%.

The unequal mixtures of amisulpride enantiomers (or a pharmaceuticallyacceptable salt of one or more of the enantiomers) of the presentinventions are, in various embodiments, combined with carrier materialsto produce a composition in a single dosage form can be varied dependingupon a variety of factors, including the subject treated and theparticular mode of administration. It should also be understood that aspecific dosage and treatment regimen for any particular subject willdepend upon a variety of factors, including the age, body weight,general health, sex, and diet of the subject, the time ofadministration, rate of excretion, drug combination, and the judgment ofthe treating physician and the severity of the particular disease ordisorder being treated.

In various aspects and embodiments, the present inventions providepharmaceutical compositions comprising:

a pharmaceutically acceptable excipient; and

a combined amount of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, and (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, in the enantiomeric ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride of about 85:15 by weight offree base. In some embodiments, the ratio of R:S is about 63:37 to about95:5 by weight of free base. In some embodiments, the ratio of R:S isabout 77:23 to about 93:7 by weight of free base. In some embodiments,the ratio of R:S is about 74:26 to about 92:8 by weight of free base. Insome embodiments, the ratio of R:S is about 65:35 to about 88:12 byweight of free base. In some embodiments, the ratio of R:S is about75:25 to about 88:12 by weight of free base. In some embodiments, theratio of R:S is about 80:20 to about 88:12 by weight of free base. Insome embodiments, the ratio of R:S is about 80:20 to about 90:10 byweight of free base.

In various aspects and embodiments, the present inventions providecompositions comprising an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, wherethe amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride, and the ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof. Invarious embodiments, the amount of (S)-amisulpride is selected toachieve a dopamine D₂ receptor occupancy level of between about 20% toabout 60%, and in various embodiments preferably between about 30% andabout. 50%; and the amount of (R)-amisulpride is selected to achieve oneor more of: (a) a suppression of rapid eye movement (REM) sleep bygreater than about 10 minutes, in various embodiments preferably greaterthan about 20 minutes or more, and in various embodiments preferablybetween about 15 minutes and about 45 minutes; (b) suppression of rapideye movement (REM) sleep by increasing the latency to REM sleep by anamount greater than about 10 minutes, in various embodiments greaterthan about 20 minutes, and in various embodiments greater than about 30minutes; and (c) a decrease in total REM sleep time relative to totalsleep time by an amount greater than about 5%.

Dopamine D₂ receptor occupancy can be measured, for example, by D2Positron Emission Tomography (PET) in human brain through the averageoccupancy observed in a group of humans of sufficient number to providestatistical significance of the result. Suppression of REM sleep can bemeasured, for example, by polysomnography (PSG) in human subjectsthrough the average inhibition observed in a group of humans ofsufficient number to provide statistical significance of the result.

In various aspects, the compositions of the present inventions comprisean unequal mixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, where the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride,and the ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, is in a ratio effective toprovide in a subject after administration: an occupancy of dopamine D2receptors between about 20% and about 60%; and a suppression of time inrapid eye movement (REM) sleep is characterized, for example, by one ormore of: (a) a decrease in REM sleep by an amount greater than about 10minutes; (b) a latency to REM sleep by an amount greater than about 10minutes, and (c) a decrease in total REM sleep time relative to totalsleep time by an amount greater than about 5%.

In various embodiments, the ratio of (R)-amisulpride to (S)-amisulpride,or pharmaceutically acceptable salts thereof, is in a ratio effective toprovide an occupancy of dopamine D2 receptors between about 30% andabout 50%.

In various embodiments, the ratio of (R)-amisulpride to (S)-amisulpride,or pharmaceutically acceptable salts thereof, is in a ratio effective toprovide one or more of: (i) a decrease in REM sleep by an amount greaterthan about 10 minutes; (ii) a decrease in REM sleep by an amount greaterthan about 20 minutes; (iii) a decrease in REM sleep by an amountbetween about 15 minutes and about 45 minutes; and (iv) a decrease inREM sleep by an amount between about 15 minutes and about 30 minutes.

In various embodiments, the ratio of (R)-amisulpride to (S)-amisulpride,or pharmaceutically acceptable salts thereof, is in a ratio effective toprovide one or more of: (i) a latency to REM sleep by an amount greaterthan about 10 minutes; (ii) a latency to REM sleep by an amount greaterthan about 20 minutes; and (iii) a latency to REM sleep by an amountgreater than about 30 minutes.

In various embodiments, the ratio of (R)-amisulpride to (S)-amisulpride,or pharmaceutically acceptable salts thereof, is in a ratio effective toprovide one or more of: (i) a decrease in total REM sleep time relativeto total sleep time by an amount greater than about 5%; (ii) a decreasein total REM sleep time relative to total sleep time by an amountgreater than about 6.5%; and (iii) a decrease in total REM sleep timerelative to total sleep time by an amount greater than about 8%.

In various embodiments of the present inventions comprising an unequalmixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, where the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride,the combined amount of (R)-amisulpride and (S)-amisulpride is betweenabout 50 mg and about 1000 mg, in various embodiments between about 200mg and about 700 mg, and in various embodiments preferably between about350 mg and about 700 mg. In various embodiments, the combined amount of(R)-amisulpride and (S)-amisulpride is about: 50 mg, 75 mg, 100 mg, 125mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg.

In various embodiments of the present inventions comprising an unequalmixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, where the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride,the ratio of (R)-amisulpride to (S)-amisulpride, or pharmaceuticallyacceptable salts thereof, is in the range between about 80:20 to about90:10 by weight. In various embodiments, the ratio of (R)-amisulpride to(S)-amisulpride, or pharmaceutically acceptable salts thereof, by weightis about: 80:20, 81:19, 82:18, 83:17, 84:16, 85:15, 86:14, 87:13, 88:12,89:11, or 90:10. Preferably in various embodiments the ratio of(R)-amisulpride to (S)-amisulpride, or pharmaceutically acceptable saltsthereof, is 85:15 by weight.

In various embodiments of the present inventions comprising an unequalmixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, where the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride,the combined amount of (R)-amisulpride and (S)-amisulpride is betweenabout 50 mg and about 1000 mg, in various embodiments between about 200mg and about 700 mg, and in various embodiments preferably between about350 mg and about 700 mg. In various embodiments, the combined amount of(R)-amisulpride and (S)-amisulpride is about: 50 mg, 75 mg, 100 mg, 125mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg;and the ratio of (R)-amisulpride to (S)-amisulpride, or pharmaceuticallyacceptable salts thereof, by weight is about: 80:20, 81:19, 82:18,83:17, 84:16, 85:15, 86:14, 87:13, 88:12, 89:11, or 90:10; andpreferably 85:15 by weight. In various embodiments, the combined amountof (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mgand about 800 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 100 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 200 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about300 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 500 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg. In variousembodiments, the (R)-(+)-amisulpride is present in an amount betweenabout 170 mg to about 600 mg, and in various embodiments preferablybetween about 300 mg to about 600 mg, and the (S)-(−)-amisulpride ispresent in an amount between about 30 mg to about 105 mg, and in variousembodiments preferably between about 40 mg to about 105 mg.

In various embodiments, the combined amount of (R)-amisulpride and(S)-amisulpride is about 100 mg and the amount of (R)-amisulpride isabout 85 mg and the amount of (S)-amisulpride is about 15 mg; in variousembodiments, the combined amount of (R)-amisulpride and (S)-amisulprideis about 200 mg and the amount of (R)-amisulpride is about 170 mg andthe amount of (S)-amisulpride is about 30 mg; in various embodiments,the combined amount of (R)-amisulpride and (S)-amisulpride is about 300mg and the amount of (R)-amisulpride is about 255 mg and the amount of(S)-amisulpride is about 45 mg; in various embodiments, the combinedamount of (R)-amisulpride and (S)-amisulpride is about 400 mg and theamount of (R)-amisulpride is about 340 mg and the amount of(S)-amisulpride is about 60 mg; in various embodiments, the combinedamount of (R)-amisulpride and (S)-amisulpride is about 500 mg and theamount of (R)-amisulpride is about 425 mg and the amount of(S)-amisulpride is about 75 mg; in various embodiments, the combinedamount of (R)-amisulpride and (S)-amisulpride is about 600 mg and theamount of (R)-amisulpride is about 510 mg and the amount of(S)-amisulpride is about 90 mg; in various embodiments, the combinedamount of (R)-amisulpride and (S)-amisulpride is about 700 mg and theamount of (R)-amisulpride is about 595 mg and the amount of(S)-amisulpride is about 105 mg.

In various aspects, the compositions of the present inventions comprisean unequal mixture of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, and (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, in a combined amount between about 50 mg andabout 1000 mg, in various embodiments between about 350 mg and about 700mg; and one or more of where: (a) the enantiomeric ratio of(R)-amisulpride to (S)-amisulpride is about 85:15 by weight; and (b) thecombined amount of (R)-amisulpride and (S)-amisulpride is present anamount effective to provide in a subject after administration anoccupancy of dopamine D2 receptors between about 20% and about 60%; anda suppression of time in rapid eye movement (REM) sleep ischaracterized, for example, by one or more of: (i) a decrease in REMsleep by an amount greater than about 10 minutes, (ii) a decrease in REMsleep by an amount greater than about 20 minutes; and (iii) a decreasein REM sleep by an amount between about 15 minutes and about 45 minutes.In various embodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 100 mg and about 800 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 100 mg and about 600 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 100 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about200 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 300 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 400 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about500 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 700 mg.

In various embodiments of aspects of the present inventions, where thecombined amount of (R)-amisulpride and (S)-amisulpride is between about50 mg and about 1000 mg, in various embodiments between about 200 mg andabout 700 mg, and in various embodiments preferably between about 400 mgand about 700 mg; the combined amount of (R)-amisulpride and(S)-amisulpride is about: 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg,200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg,425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg,650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg,875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg.

In various embodiments of aspects of the present inventions, where thecombined amount of (R)-amisulpride and (S)-amisulpride is between about50 mg and about 1000 mg, in various embodiments between about 200 mg andabout 700 mg, and in various embodiments preferably between about 350 mgand about 700 mg, and the combined amount of (R)-amisulpride and(S)-amisulpride is present an amount effective to provide in a subjectafter administration an occupancy of dopamine D2 receptors between about20% and about 60%; and a suppression of time in rapid eye movement (REM)sleep is characterized, for example, by one or more of: (a) a decreasein REM sleep by an amount greater than about 10 minutes; the ratio of(R)-amisulpride to (S)-amisulpride, or pharmaceutically acceptable saltsthereof, by weight of free base is about: 80:20, 81:19, 82:18, 83:17,84:16, 85:15, 86:14, 87:13, 88:12, 89:11, or 90:10; and preferably 85:15by weight of free base. In various embodiments, the ratio of(R)-amisulpride to (S)-amisulpride, or pharmaceutically acceptable saltsthereof, by weight of free base is about: 63:37, 65:35, 74:26, 75:35,77:23, 80:20, 88:12, 95:5, 93:7, or 92:8. In various embodiments, theratio of (R)-amisulpride to (S)-amisulpride, or pharmaceuticallyacceptable salts thereof, by weight of free base is about: 63:37-95:5,65:35-88:12, 74:26-92:8, 75:35-88:12, 77:23-93:7, or 80:20-88:12. Invarious embodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 100 mg and about 800 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 100 mg and about 600 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 100 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about200 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 300 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 400 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about500 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 700 mg.

In various aspects, the compositions of the present inventions comprisean unequal mixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, where the amount of(R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulpride,and the ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, is in a ratio effective toprovide in a subject after administration inhibition of dopamine D2activity and serotonin 5-HT7 activity in said subject such that theratio of the serotonin 5-HT7 receptor inhibitory constant to thedopamine D2 receptor inhibitory constant is in the range between about 2to about 6. In various embodiments, the ratio of the serotonin 5-HT7receptor inhibitory constant to the dopamine D2 receptor inhibitoryconstant is in the range between about 3 to about 5. In variousembodiments, the ratio of the serotonin 5-HT7 receptor inhibitoryconstant to the dopamine D2 receptor inhibitory constant is about 4.

In various embodiments of aspects of the present inventions, where theratio of (R)-amisulpride to (S)-amisulpride, or pharmaceuticallyacceptable salts thereof, is in a ratio effective to provide in asubject after administration inhibition of dopamine D2 activity andserotonin 5-HT7 activity in said subject such that the ratio of theserotonin 5-HT7 receptor inhibitory constant to the dopamine D2 receptorinhibitory constant is in the range between about 2 to about 6, and invarious embodiments between about 3 to about 5; the combined amount of(R)-amisulpride and (S)-amisulpride is between about 50 mg and about1000 mg, in various embodiments between about 200 mg and about 700 mg,and in various embodiments preferably between about 350 mg and about 700mg, and in various embodiments, the combined amount of (R)-amisulprideand (S)-amisulpride is about: 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 100 mg and about 800 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 100 mg and about 600 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 100 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about200 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 300 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 400 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about500 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 700 mg.

In various embodiments of aspects of the present inventions, where theratio of (R)-amisulpride to (S)-amisulpride, or pharmaceuticallyacceptable salts thereof, is in a ratio effective to provide in asubject after administration inhibition of dopamine D2 activity andserotonin 5-HT7 activity in said subject such that the ratio of theserotonin 5-HT7 receptor inhibitory constant to the dopamine D2 receptorinhibitory constant is in the range between about 2 to about 6, and invarious embodiments between about 3 to about 5; the ratio of(R)-amisulpride to (S)-amisulpride, or pharmaceutically acceptable saltsthereof, by weight is about: 80:20, 81:19, 82:18, 83:17, 84:16, 85:15,86:14, 87:13, 88:12, 89:11, or 90:10; and preferably 85:15 by weight offree base.

In various embodiments of aspects of the present inventions, where theratio of (R)-amisulpride to (S)-amisulpride, or pharmaceuticallyacceptable salts thereof, is in a ratio effective to provide in asubject after administration inhibition of dopamine D2 activity andserotonin 5-HT7 activity in said subject such that the ratio of theserotonin 5-HT7 receptor inhibitory constant to the dopamine D2 receptorinhibitory constant is in the range between about 2 to about 6, and invarious embodiments between about 3 to about 5; the combined amount of(R)-amisulpride and (S)-amisulpride is between about 50 mg and about1000 mg, in various embodiments between about 200 mg and about 700 mg,and in various embodiments preferably between about 350 mg and about 700mg, and in various embodiments, the combined amount of (R)-amisulprideand (S)-amisulpride is about: 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg; and the ratio of(R)-amisulpride to (S)-amisulpride, or pharmaceutically acceptable saltsthereof, by weight is about: 80:20, 81:19, 82:18, 83:17, 84:16, 85:15,86:14, 87:13, 88:12, 89:11, or 90:10; and preferably 85:15 by weight. Invarious embodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 100 mg and about 800 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 100 mg and about 600 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 100 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about200 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 300 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 400 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about500 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 700 mg. In various embodiments, the(R)-amisulpride is present in an amount between about 300 mg to about600 mg, and the (S)-amisulpride is present in an amount between about 40mg to about 105 mg.

It is to be understood, that in various aspects and embodiments, thevarious embodiments of the medicaments and compositions of the presentinventions can be used to treat a psychiatric disorder in a subject, aneurological disorder in a subject, or both a neurological disorder anda psychiatric disorder, the disorder including, but not limited to, oneor more of a mood disorder, bipolar disorder (BPD), depression, bipolardepression, major depressive episodes associated with bipolar Idisorder, major depressive disorder (MDD), as an adjunctive treatment ofmajor depressive disorder; major depressive disorder with mixed features(MDD-MF), treatment resistant depression (TRD), schizophrenia, negativesymptoms of schizophrenia, and schizoaffective disorder.

In various aspects, the present inventions provide a method of treatinga psychiatric disorder in a subject comprising administering acomposition comprising a R dominant amisulpride mixture where themixture is administered in a therapeutically effective amount to providein a subject after administration: an occupancy of dopamine D2 receptorsbetween about 20% and about 60%; and a suppression of time in rapid eyemovement (REM) sleep is characterized, for example, by one or more of:(a) a decrease in REM sleep by an amount greater than about 10 minutes,in various embodiments preferably greater than about 20 minutes or more,and in various embodiments preferably between about 15 minutes and about45 minutes; (b) suppression of rapid eye movement (REM) sleep byincreasing the latency to REM sleep by an amount greater than about 10minutes, in various embodiments greater than about 20 minutes, and invarious embodiments greater than about 30 minutes; and (c) a decrease intotal REM sleep time relative to total sleep time by an amount greaterthan about 5%.

In various embodiments, the ratio of (R)-amisulpride to (S)-amisulpride,or pharmaceutically acceptable salts thereof, is in a ratio effective toprovide an occupancy of dopamine D2 receptors between about 30% andabout 50%.

Dopamine D₂ receptor occupancy can be measured, for example, by D2Positron Emission Tomography (PET) in human brain through the averageoccupancy observed in a group of humans of sufficient number to providestatistical significance of the result. Suppression of REM sleep can bemeasured, for example, by polysomnography (PSG) in human subjectsthrough the average inhibition observed in a group of humans ofsufficient number to provide statistical significance of the result.

In various aspects, the present inventions provide a method of treatinga psychiatric disorder in a subject comprising administering acomposition comprising a R dominant amisulpride mixture where themixture is administered in a therapeutically effective amount to providein a subject after administration: inhibition of dopamine D2 activityand serotonin 5-HT7 activity in said subject such that the ratio of theserotonin 5-HT7 receptor inhibitory constant to the dopamine D2 receptorinhibitory constant is in the range between about 2 to about 6. Invarious embodiments, the ratio of the serotonin 5-HT7 receptorinhibitory constant to the dopamine D2 receptor inhibitory constant isin the range between about 3 to about 5, and in various embodiments, theratio of the serotonin 5-HT7 receptor inhibitory constant to thedopamine D2 receptor inhibitory constant is about 4.

In various embodiments, of aspects and embodiments of the presentinventions for treating a psychiatric disorder in subject comprisingadministering a R dominant amisulpride mixture, the mixture comprises aratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, that is in the range between about 80:20 toabout 90:10 by weight. In various embodiments, the ratio of(R)-amisulpride to (S)-amisulpride, or pharmaceutically acceptable saltsthereof, by weight is about: 80:20, 81:19, 82:18, 83:17, 84:16, 85:15,86:14, 87:13, 88:12, 89:11, or 90:10. Preferably in various embodimentsthe ratio of (R)-amisulpride to (S)-amisulpride, or pharmaceuticallyacceptable salts thereof, is 85:15 by weight.

In various embodiments, of aspects and embodiments of the presentinventions for treating a psychiatric disorder in subject comprisingadministering a R dominant amisulpride mixture, the mixture comprises atotal combined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride isbetween about 50 mg and about 1000 mg, in various embodiments betweenabout 200 mg and about 700 mg, and in various embodiments preferablybetween about 350 mg and about 700 mg. In various embodiments, thecombined amount of (R)-amisulpride and (S)-amisulpride is about: 50 mg,75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg,300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg,525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg,750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg,975 mg, or 1000 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 800 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 100 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 200 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about300 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 500 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg.

In various embodiments, of aspects and embodiments of the presentinventions for treating a psychiatric disorder in subject comprisingadministering a R dominant amisulpride mixture, the mixture comprises atotal combined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride isbetween about 50 mg and about 1000 mg, in various embodiments betweenabout 200 mg and about 700 mg, and in various embodiments preferablybetween about 350 mg and about 700 mg. In various aspects, the presentinventions provide a method of treating a psychiatric disorder in asubject comprising administering a pharmaceutical composition comprisingone or more pharmaceutically excipient, carrier, adjuvant, or vehicle,and a combined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpridebetween about 50 mg and about 1000 mg, in various embodiments betweenabout 200 mg and about 700 mg, and in various embodiments preferablybetween about 350 mg and about 700 mg. In various embodiments, suchcomposition comprises a ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, thatis in the range between about 80:20 to about 90:10 by weight; andpreferably in various embodiments the ratio is about 85:15 by weight. Invarious embodiments, the combined amount of (R)-amisulpride and(S)-amisulpride is about: 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg,200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg,425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg,650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg,875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg; and the ratio of(R)-amisulpride to (S)-amisulpride, or pharmaceutically acceptable saltsthereof, by weight is about: 80:20, 81:19, 82:18, 83:17, 84:16, 85:15,86:14, 87:13, 88:12, 89:11, or 90:10; and preferably 85:15 by weight. Invarious embodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 100 mg and about 800 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 100 mg and about 600 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 100 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about200 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 300 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 400 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about500 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 700 mg. In various embodiments, the(R)-(+)-amisulpride is present in an amount between about 300 mg toabout 600 mg, and the (S)-(−)-amisulpride is present in an amountbetween about 40 mg to about 105 mg.

In various aspects, the present inventions provide medicaments for andprovide methods of treating a psychiatric disorder in a human subject,comprising administering on a treatment cycle an amount of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, andan amount of (S)-(−)-amisulpride, or a pharmaceutically acceptable saltthereof, in a combined amount between about 50 mg and about 1000 mg, invarious embodiments between about 200 mg and about 700 mg, and invarious embodiments preferably between about 350 mg and about 700 mg pertreatment cycle to a human subject in need thereof, wherein the amountof (R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulprideduring the treatment cycle. In various embodiments, the enantiomericratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride over a treatmentcycle of the combined amount is in the range between about 80:20 toabout 90:10 by weight of free base. In various embodiments, the ratio ofR:S is in the range between about: 65:35-88:12, 75:25-88:12, or80:20-88:12 by weight of free base. In various embodiments, the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about100 mg and about 800 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 100 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 200 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about300 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 500 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg.

In various embodiments, the combined amount of (R)-amisulpride and(S)-amisulpride per treatment cycle is about: 50 mg, 75 mg, 100 mg, 125mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg;and the enantiomeric ratio of (R)-amisulpride to (S)-amisulpride, orpharmaceutically acceptable salts thereof, over a treatment cycle of thecombined amount is, by weight, about: 80:20, 81:19, 82:18, 83:17, 84:16,85:15, 86:14, 87:13, 88:12, 89:11, or 90:10; and preferably 85:15 byweight.

In various aspects, the present inventions provide medicaments for andprovide methods of inhibiting dopamine D2 activity and serotonin 5-HT7activity in a subject comprising administering to a subject an effectiveamount of an unequal mixture of (R)-(+)-amisulpride, or apharmaceutically acceptable salt thereof, and (S)-(−)-amisulpride, or apharmaceutically acceptable salt thereof. In various embodiments, theinhibition of dopamine D2 activity and the inhibition serotonin 5-HT7activity comprises: an occupancy of dopamine D2 receptors between about20% to about 60%, and in various embodiments preferably between about30% and about. 50%; and a suppression of the time in rapid eye movement(REM) sleep as characterized by one or more of: (a) a decrease in REMsleep by an amount greater than about 10 minutes, in various embodimentspreferably greater than about 20 minutes or more, and in variousembodiments preferably between about 15 minutes and about 45 minutes,(b) a latency to REM sleep by an amount greater than about 10 minutes,in various embodiments greater than about 20 minutes, and in variousembodiments greater than about 30 minutes; or (c) a decrease in totalREM sleep time relative to total sleep time by an amount greater thanabout 5%.

In various embodiments of the methods of inhibiting dopamine D2 activityand serotonin 5-HT7 activity in a subject, the unequal mixture of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, and(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof,comprises an amount of (R)-(+)-amisulpride that is greater than theamount of (S)-(−)-amisulpride, and in various embodiments, the ratio of(R)-amisulpride to (S)-amisulpride, or pharmaceutically acceptable saltsthereof, by weight is about: 80:20, 81:19, 82:18, 83:17, 84:16, 85:15,86:14, 87:13, 88:12, 89:11, or 90:10; and preferably 85:15 by weight.

In various embodiments of the methods of inhibiting dopamine D2 activityand serotonin 5-HT7 activity in a subject, the unequal mixture of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, and(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof, theof (R)-amisulpride, or a pharmaceutically acceptable salt thereof, and(S)-amisulpride, or a pharmaceutically acceptable salt thereof, in arepresent in a combined amount between about 50 mg and about 1000 mg, invarious embodiments between about 200 mg and about 700 mg, and invarious embodiments preferably between about 350 mg and about 700 mg andthe amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride. In various embodiments, the combined amount of(R)-amisulpride and (S)-amisulpride is about: 50 mg, 75 mg, 100 mg, 125mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg.In various embodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 100 mg and about 800 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 100 mg and about 600 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 100 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about200 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 300 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 400 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about500 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 700 mg.

In various embodiments of the methods of inhibiting dopamine D2 activityand serotonin 5-HT7 activity in a subject, the unequal mixture of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, and(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof, theof (R)-amisulpride, or a pharmaceutically acceptable salt thereof, and(S)-amisulpride, or a pharmaceutically acceptable salt thereof, in arepresent in a combined amount between about 50 mg and about 1000 mg, invarious embodiments between about 200 mg and about 700 mg, and invarious embodiments preferably between about 350 mg and about 700 mg andthe amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride. In various embodiments, the combined amount of(R)-amisulpride and (S)-amisulpride is about: 50 mg, 75 mg, 100 mg, 125mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg;and the ratio of (R)-amisulpride to (S)-amisulpride, or pharmaceuticallyacceptable salts thereof, by weight is about: 80:20, 81:19, 82:18,83:17, 84:16, 85:15, 86:14, 87:13, 88:12, 89:11, or 90:10; andpreferably 85:15 by weight. In various embodiments, the combined amountof (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mgand about 800 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 100 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 200 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about300 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 500 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg. In variousembodiments, the (R)-(+)-amisulpride is present in an amount betweenabout 300 mg to about 600 mg, and the (S)-(−)-amisulpride is present inan amount between about 40 mg to about 105 mg.

It is to be understood, that in various aspects and embodiments, thevarious embodiments of the compositions of the present inventions can beused to treat, and used to manufacture a medicament to treat, apsychiatric disorder, a neurological disorder, or both a neurologicaldisorder and a psychiatric disorder, the disorder including, but notlimited to, one or more of a mood disorder, bipolar disorder (BPD),depression, bipolar depression, major depressive episodes associatedwith bipolar I disorder, major depressive disorder (MDD), as anadjunctive treatment of major depressive disorder; major depressivedisorder with mixed features (MDD-MF), treatment resistant depression(TRD), schizophrenia, negative symptoms of schizophrenia, andschizoaffective disorder.

In various aspects, the present inventions provide compositions andmedicaments comprising a R dominant amisulpride mixture used for thetreatment of a psychiatric disorder, a neurological disorder, or both,comprise a R dominant amisulpride mixture where the ratio of theserotonin 5-HT7 receptor inhibitory constant measured in vitro to thedopamine D2 receptor inhibitory constant measured in vitro is in therange between about 2 to about 6. In various embodiments, in vitro theratio of the serotonin 5-HT7 receptor inhibitory constant to thedopamine D2 receptor inhibitory constant is in the range between about 3to about 5, and in various embodiments, the in vitro ratio of theserotonin 5-HT7 receptor inhibitory constant to the dopamine D2 receptorinhibitory constant is about 4.

In various embodiments, of aspects and embodiments of the presentinventions compositions and medicaments comprising a R dominantamisulpride mixture, used for the treatment of a psychiatric disorder, aneurological disorder, or both, the amisulpride mixture comprises aratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, that is in the range between about 80:20 toabout 90:10 by weight. In various embodiments, the ratio of(R)-amisulpride to (S)-amisulpride, or pharmaceutically acceptable saltsthereof, by weight is about: 80:20, 81:19, 82:18, 83:17, 84:16, 85:15,86:14, 87:13, 88:12, 89:11, or 90:10. Preferably in various embodimentsthe ratio of (R)-amisulpride to (S)-amisulpride, or pharmaceuticallyacceptable salts thereof, is 85:15 by weight.

In various embodiments, of aspects and embodiments of the presentinventions compositions and medicaments comprising a R dominantamisulpride mixture one or more pharmaceutically excipient, carrier,adjuvant, or vehicle, used for the treatment of a psychiatric disorder,a neurological disorder, or both, the amisulpride mixture comprises atotal combined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride isbetween about 50 mg and about 1000 mg, in various embodiments betweenabout 200 mg and about 700 mg, and in various embodiments preferablybetween about 350 mg and about 700 mg. In various embodiments, thecombined amount of (R)-amisulpride and (S)-amisulpride is about: 50 mg,75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg,300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg,525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg,750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg,975 mg, or 1000 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 800 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 100 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 200 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about300 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 500 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg.

In various embodiments, of aspects and embodiments of the presentinventions compositions and medicaments comprising a R dominantamisulpride mixture, used for the treatment of a psychiatric disorder, aneurological disorder, or both, the amisulpride mixture comprises atotal combined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride isbetween about 50 mg and about 1000 mg, in various embodiments betweenabout 200 mg and about 700 mg, and in various embodiments preferablybetween about 350 mg and about 700 mg.

In various aspects, the present inventions provide compositions andmedicaments comprising a R dominant amisulpride mixture, used for thetreatment of a psychiatric disorder, a neurological disorder, or both,the composition or medicament comprises one or more pharmaceuticallyexcipient, carrier, adjuvant, or vehicle, and a combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 50 mg andabout 1000 mg, in various embodiments between about 200 mg and about 700mg, and in various embodiments preferably between about 350 mg and about700 mg. In various embodiments, such compositions and medicamentscomprise a ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, that is in the range betweenabout 80:20 to about 90:10 by weight; and preferably in variousembodiments the ratio is about 85:15 by weight. In various embodiments,the combined amount of (R)-amisulpride and (S)-amisulpride is about: 50mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950mg, 975 mg, or 1000 mg; and the ratio of (R)-amisulpride to(S)-amisulpride, or pharmaceutically acceptable salts thereof, by weightis about: 80:20, 81:19, 82:18, 83:17, 84:16, 85:15, 86:14, 87:13, 88:12,89:11, or 90:10; and preferably 85:15 by weight. In various embodiments,the combined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride isbetween about 100 mg and about 800 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride isbetween about 100 mg and about 600 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about100 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 200 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 300 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about400 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 500 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 600 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about700 mg. In various embodiments, the (R)-(+)-amisulpride is present in anamount between about 300 mg to about 600 mg, and the (S)-(−)-amisulprideis present in an amount between about 40 mg to about 105 mg.

In various embodiments of the methods of inhibiting dopamine D2 activityand serotonin 5-HT7 activity in a subject, the inhibition takes place ina subject suffering from one or more psychiatric disorders, the unequalmixture of (R)-(+)-amisulpride, or a salt thereof, and(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof ispresent in a therapeutically effective amount.

The compositions of the present inventions are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the subject to be treated. Itwill be understood, however, that the total daily usage of thecompositions of the present inventions will be decided by the attendingphysician within the scope of sound medical judgment.

In various aspects, the present inventions provide medicaments for andprovide methods of treating a psychiatric disorder in a human subject,comprising administering on a treatment cycle an amount of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, andan amount of (S)-(−)-amisulpride, or a pharmaceutically acceptable saltthereof, in a combined amount between about 50 mg and about 1000 mg, invarious embodiments between about 200 mg and about 700 mg, and invarious embodiments preferably between about 350 mg and about 700 mg pertreatment cycle to a human subject in need thereof, wherein the amountof (R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulprideduring the treatment cycle. In various embodiments, the combined amountof (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mgand about 800 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 100 mg andabout 600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 100 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 200 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about300 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg. In variousembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is about 500 mg. In various embodiments, thecombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about600 mg. In various embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg. In variousembodiments, the enantiomeric ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride over a treatment cycle of the combined amount is inthe range between about 80:20 to about 90:10 by weight of free base; andpreferably in various embodiments the ratio is about 85:15 by weight offree base. In various embodiments, the ratio of R:S is in the rangebetween about: 65:35-88:12, 75:25-88:12, or 80:20-88:12 by weight offree base. In various embodiments, the (R)-amisulpride, or apharmaceutically acceptable salt thereof, and the (S)-amisulpride, or apharmaceutically acceptable salt thereof, are given separately during atreatment cycle.

It is to be understood that the composition can be administered over atreatment cycle as a single dosage unit form, comprising both(R)-amisulpride and the (S)-amisulpride enantiomers, in separate dosageunit forms comprising only one of the amisulpride enantiomers, or acombination thereof. For example, in various embodiments, the(R)-amisulpride, or a pharmaceutically acceptable salt thereof, and the(S)-amisulpride, or a pharmaceutically acceptable salt thereof, aregiven separately during a treatment cycle.

In addition, it is to be understood that the administration of an amountof the composition over a treatment cycle may be provided in a multipledosage regimen. For example, in various embodiments, a multiple dosageregimen comprises dosage with two or more dosage unit formssubstantially simultaneously; dosage with two or more dosage unit formssequentially; dosage with two or more dosage unit forms within a periodof time from one another, preferably in various embodiments within 4 to48 hours from one another; and combinations thereof.

For example, in various embodiments, the treatment cycle is two days,where the total S-enantiomer dosage amount is given once per treatmentcycle (to, for example, maintain D2 occupancy at therapeutic levels) andthe total R-enantiomer dosage amount is given up to three times per day(e.g. up to six times per treatment cycle at roughly equally spacedintervals), in various preferred embodiments in roughly equal dosageamounts per dose (to, for example, maintain desired plasma levels andhave 5-HT7 effects throughout the day).

In various embodiments of the present inventions, the treatment cycle isdaily and the administration occurs: (a) once per day; (b) twice perday; (c) thrice per day; or (d) four times per day. In variousembodiments of the present inventions, the treatment cycle is every twodays.

In various embodiments, the enantiomeric ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride over a treatment cycle is about 85:15 by weight offree base, the treatment cycle is daily and the total amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 200 mg over thetreatment cycle. In various embodiments, the enantiomeric ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride over a treatment cycle isabout 85:15 by weight of free base, the treatment cycle is daily and thetotal amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400mg over the treatment cycle.

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Ed.,hereinafter, the “DSM-5”), published by the American PsychiatricAssociation in 2013, and is incorporated herein by reference, provides astandard diagnostic system upon which persons of skill rely fordiagnosis of various diseases and disorders.

In various aspects, the disease or disorder which the medicaments andmethods of the present inventions treat comprises one or more of apsychiatric disorder; mood disorder; depressive disorder; bipolardisorder; bipolar depression (e.g. major depressive episodes associatedwith bipolar I disorder), schizophrenia; schizoaffective disorder;anxiety disorder; obsessive-compulsive disorder; behavior disturbancesassociated with a neurocognitive disorder; conduct disorder;neurological disorder; medication-induced movement disorder; and motordisorder.

In various embodiments, the neurological or psychiatric disease ordisorder is one or more of a mood disorder, bipolar disorder (BPD),depression, bipolar depression, major depressive episodes associatedwith bipolar I disorder, major depressive disorder (MDD), as anadjunctive treatment of major depressive disorder, major depressivedisorder with mixed features (MDD-MF), treatment resistant depression(TRD), schizophrenia, negative symptoms of schizophrenia, treatmentresistant depression (TRD) and schizoaffective disorder.

In various embodiments, the neurological or psychiatric disease ordisorder is selected from a psychosis, including schizophrenia(paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-induced ordrug-induced (e.g., phencyclidine, ketamine and other dissociativeanesthetics, amphetamine and other psychostimulants and cocaine)psychotic disorder, psychosis disorder, psychosis associated withaffective disorders, brief reactive psychosis, schizoaffectivepsychosis, “schizophrenia-spectrum” disorders such as schizoid orschizotypal personality disorders, or illnesses with associatedpsychosis (such as major depression, manic depressive (bipolar)disorder, Alzheimer's disease and post-traumatic stress syndrome),including both positive, negative, and cognitive symptoms ofschizophrenia and other psychoses; anxiety disorders including acutestress disorder, agoraphobia, generalized anxiety disorder,obsessive-compulsive disorder and related disorders including bodydysmorphic disorder, hoarding disorder, trichotillomania, andexcoriation disorder, panic attack, panic disorder, post-traumaticstress disorder, separation anxiety disorder, social phobia, specificphobia, substance-induced anxiety disorder and anxiety due to a generalmedical condition; substance-related disorders and addictive behaviors(including substance-induced delirium, persisting dementia, persistingamnestic disorder, psychotic disorder or anxiety disorder; tolerance,dependence or withdrawal from substances including alcohol,amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine,opioids, phencyclidine, sedatives, hypnotics or anxiolytics); eatingdisorders such as obesity, bulimia nervosa, pica and compulsive eatingdisorders; bipolar disorders, including, bipolar depression, bipolar Idisorder, bipolar II disorder, cyclothymic disorder, substance/medication-induced bipolar and related disorders, bipolar andrelated disorder due to another medical condition, other specifiedbipolar and related disorder, and unspecified bipolar and relateddisorders, depressive disorders including, but not limited to, unipolardepression, seasonal depression and post-partum depression, atypicaldepression, catatonic depression, elderly depression, endogenousdepression, melancholic depression, perinatal depression, situationaldepression, chronic depression, bipolar depression, major depressivedisorder (MDD), as an adjunctive treatment MDD, major depressivedisorder with anxious distress, MDD with mixed features (MDD-MF), MDDwith melancholic features, MDD with atypical features, MDD withmood-congruent psychotic features, MDD with mood-incongruent psychoticfeatures, MDD with catatonia, with peripartum onset, MDD with seasonalpattern, treatment resistant depression (TRD), and persistent depressivedisorder (dysthymia), and are associated with depressed mood (sadness),poor concentration, insomnia, fatigue, appetite disturbances, excessiveguilt and thoughts of suicide, premenstrual syndrome (PMS) andpremenstrual dysphoric disorder (PDD), mood disorders due to a generalmedical condition, and substance-induced mood disorders; and sleepdisorders including insomnia, disturbed sleep, jet lag, hypersomnia,cataplexy, sleep apnea, obstructive sleep apnea, REM sleep behaviordisorder, Restless Leg Syndrome, periodic limb movement disorder,circadian rhythm sleep disorders, delayed sleep phase disorder,sleepwalking, night terrors, bed wetting, rapid eye movement sleepbehavior disorder, shift work sleep disorder, excessive daytimesleepiness, non-24-hour sleep-wake disorder, sleep paralysis andnarcolepsy.

Psychiatric disorders are pathological conditions of the braincharacterized by identifiable symptoms that result in abnormalities incognition, emotion or mood, or the highest integrative aspects ofbehavior. These disorders may vary in severity of symptoms, duration,and functional impairment. Psychiatric disorders afflict millions ofpeople worldwide resulting in tremendous human suffering and economicburden due to lost productivity. Mood disorders are a type ofpsychiatric disorder often defined as a group of heterogeneous,typically recurrent illnesses including unipolar (depressive) andbipolar (manic-depressive) disorders characterized by pervasive mooddisturbances, psychomotor dysfunction, and vegetative symptoms. Suicide,the most serious complication in patients with mood disorders, is thecause of death in 15 to 25% of untreated patients with mood disorders;unrecognized or inadequately treated depression contributes to 50 to 70%of all completed suicides.

The term “mood disorder” as used herein includes depression, majordepression, major depressive disorder, mild depression, severedepression without psychosis, severe depression with psychosis,melancholia (formerly endogenous depression), atypical depression,dysthymic disorder, manic depression, bipolar disorder, bipolardepression (e.g. major depressive episodes associated with bipolar Idisorder), bipolar I disorder, bipolar II disorder, bipolar IIIdisorder, cyclothymic disorder, and chronic hypomania.

In various embodiments, the neurological or psychiatric disease ordisorder is a bipolar disorder. Bipolar disorders (including bothbipolar I and bipolar II) are serious psychiatric disorders that have aprevalence of approximately 2% of the population, and affects bothgenders alike. It is a relapsing-remitting condition characterized bycycling between elevated (i.e., manic) and depressed moods, whichdistinguishes it from other disorders such as major depressive disorderand schizophrenia. Bipolar I is defined by the occurrence of a fullmanic episode, although most individuals experience significantdepression. Symptoms of mania include elevated or irritable mood,hyperactivity, grandiosity, decreased need for sleep, racing thoughtsand in some cases, psychosis. The depressive episodes are characterizedby anhedonia, sad mood, hopelessness, poor self-esteem, diminishedconcentration and lethargy. Bipolar II is defined as the occurrence of amajor depressive episode and hypomanic (less severe mania) episodealthough patients spend considerable more time in the depressive state.Other related conditions include cyclothymic disorder.

In bipolar I disorder, full-fledged manic and major depressive episodesalternate. Bipolar I disorder commonly begins with depression and ischaracterized by at least one manic or excited period during its course.The depressive phase can be an immediate prelude or aftermath of mania,or depression and mania can be separated by months or years.

In bipolar II disorder, depressive episodes alternate with hypomanias(relatively mild, nonpsychotic periods of usually <1 week). During thehypomanic period, mood brightens, the need for sleep decreases, andpsychomotor activity accelerates beyond the patient's usual level.Often, the switch is induced by circadian factors (e.g., going to beddepressed and waking early in the morning in a hypomanic state).Hypersomnia and overeating are characteristic and may recur seasonally(e.g., in autumn or winter); insomnia and poor appetite occur during thedepressive phase. For some persons, hypomanic periods are adaptivebecause they are associated with high energy, confidence, andsupernormal social functioning. Many patients who experience pleasantelevation of mood, usually at the end of a depression, do not report itunless specifically questioned.

Patients with major depressive episodes and a family history of bipolardisorders often exhibit subtle hypomanic tendencies; their temperamentis termed hyperthymic (i.e., driven, ambitious, andachievement-oriented).

In cyclothymic disorder, less severe hypomanic and mini-depressiveperiods follow an irregular course, with each period lasting a few days.Cyclothymic disorder is commonly a precursor of bipolar II disorder. Butit can also occur as extreme moodiness without being complicated bymajor mood disorders. In such cases, brief cycles of retarded depressionaccompanied by low self-confidence and increased sleep alternate withelation or increased enthusiasm and shortened sleep. In another form,low-grade depressive features predominate; the bipolar tendency is shownprimarily by how easily elation or irritability is induced byantidepressants. In chronic hypomania, a form rarely seen clinically,elated periods predominate, with habitual reduction of sleep to <6hours. Persons with this form are constantly overcheerful, self-assured,overenergetic, full of plans, improvident, overinvolved, and meddlesome;they rush off with restless impulses and accost people.

Accordingly, in various embodiments, the neurological or psychiatricdisease or disorder is one or more of bipolar I disorder, bipolar IIdisorder, cyclothymic disorder, other specified bipolar and relateddisorder, or unspecified bipolar and related disorder, and bipolar Idisorder or bipolar II disorder with the specifiers of anxious distress,with mixed features, with rapid cycling, with melancholic features, withatypical features, with mood-congruent psychotic features, with moodincongruent psychotic features, with catatonia, with peripartum onset,and/or with seasonal pattern. A relatively recent article by Hu et al[Prim Care Companion CNS Disord. 2014; 16(2): PCC.13r01599] highlightsthat bipolar disorder, while commonly encountered in the primary caresetting, is often misdiagnosed or undiagnosed. The DSM-5 attempts tocapture the large proportion of patients with subsyndromal mixedsymptoms with the inclusion of the mixed specifier.

In various embodiments, the neurological or psychiatric disease ordisorder is a depressive disorder. Depressive disorders include, but arenot limited to, depressive disorders including, but not limited to,unipolar depression, seasonal depression and post-partum depression,atypical depression, catatonic depression, elderly depression,endogenous depression, melancholic depression, perinatal depression,situational depression, chronic depression, bipolar depression (e.g.,major depressive episodes associated with bipolar I disorder), majordepressive disorder (MDD), major depressive disorder with mixed features(MDD-MF), treatment resistant depression (TRD), and dysthymia, and areassociated with depressed mood (sadness), poor concentration, insomnia,fatigue, appetite disturbances, excessive guilt and thoughts of suicide,premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD),mood disorders due to a general medical condition, and substance-inducedmood disorders.

Depression is an affective disorder, the pathogenesis of which cannot beexplained by any single cause or theory. Unfortunately, treatmentoptions for depressed patients who have suboptimal clinical responses totherapy with an antidepressant are limited. Approximately thirty percent(30%) of patients initiating antidepressant therapy show suboptimal ordelayed clinical responses to the first-line antidepressant agents thatare commonly used to treat depression.

Typically, if a patient exhibits suboptimal or delayed clinical responseafter several weeks of therapy with an antidepressant, the clinician'sinitial approach is to increase the dose of the antidepressant. If thepatient's response remains unsatisfactory after increasing the dose, themost common approaches that many clinicians will pursue are: a)switching to another antidepressant; or b) adding a secondantidepressant; or c) attempting an augmentation therapy byadministering agents such as lithium carbonate, thyroid hormone(triiodothyronine), psychostimulants, modafinil, atypicalantipsychotics, buspirone, or pindolol.

In its full syndromal expression, clinical depression manifests as majordepressive disorder, with episodic course and varying degrees ofresidual manifestations between episodes. The mood is typicallydepressed, irritable, and/or anxious. The patient may appear miserable,with furrowed brows, downturned corners of the mouth, slumped posture,poor eye contact, and monosyllabic (or absent) speech. The morbid moodmay be accompanied by preoccupation with guilt, self-denigrating ideas,decreased ability to concentrate, indecisiveness, diminished interest inusual activities, social withdrawal, helplessness, hopelessness, andrecurrent thoughts of death and suicide. Sleep disorders are common. Insome, the morbid mood is so deep that tears dry up; the patientcomplains of an inability to experience usual emotions—including grief,joy, and pleasure—and of a feeling that the world has become colorless,lifeless, and dead.

Melancholia (formerly endogenous depression) is characterized by markedpsychomotor slowing (of thinking and activity) or agitation (e.g.,restlessness, wringing of the hands, pressure of speech), weight loss,irrational guilt, and loss of the capacity to experience pleasure. Moodand activity vary diurnally, with a nadir in the morning. Mostmelancholic patients complain of difficulty falling asleep, multiplearousals, and insomnia in the middle of the night or early morning.Sexual desire is often diminished or lost. Amenorrhea can occur.Anorexia and weight loss may lead to emaciation and secondarydisturbances in electrolyte balance.

In atypical depression, reverse vegetative features dominate theclinical presentation; they include anxious-phobic symptoms, eveningworsening, initial insomnia, hypersomnia that often extends into theday, and hyperphagia with weight gain. Unlike patients with melancholia,those with atypical depression show mood brightening to potentiallypositive events but often crash into a paralyzing depression with theslightest adversity. Atypical depressive and bipolar II disordersoverlap considerably.

In dysthymic disorder, depressive symptoms typically begin insidiouslyin childhood or adolescence and pursue an intermittent or low-gradecourse over many years or decades; major depressive episodes maycomplicate it (double depression). In pure dysthymia, depressivemanifestations occur at a subthreshold level and overlap considerablywith those of a depressive temperament: habitually gloomy, pessimistic,humorless, or incapable of fun; passive and lethargic; introverted;skeptical, hypercritical, or complaining; self-critical,self-reproaching, and self-derogatory; and preoccupied with inadequacy,failure, and negative events.

Thorough evaluation of many persons with depression reveals bipolartraits, and as many as one in five patients with a depressive disorderalso develops frank hypomania or mania. Most switches from unipolar tobipolar disorder occur within 5 years of the onset of depressivemanifestations. Predictors of a switch include early onset of depression(<25 years old), postpartum depression, frequent episodes of depression,quick brightening of mood with somatic treatments (e.g.,antidepressants, phototherapy, sleep deprivation, electroconvulsivetherapy), and a family history of mood disorders for three consecutivegenerations.

Between episodes, patients with bipolar disorder exhibit depressivemoodiness and sometimes high-energy activity; disruption indevelopmental and social functioning in bipolar depression is morecommon than in unipolar disorder. In bipolar disorder, depressionepisodes are shorter (3 to 6 months), age of onset is younger, onset ofepisodes is more abrupt, and cycles (time from onset of one episode tothat of the next) are shorter than in unipolar disorder. Cyclicity isparticularly accentuated in rapid-cycling forms of bipolar disorder(usually defined as >=4 episodes/year). In addition depressive episodesin bipolar disorder are a difficult component of BPD to treat. Forexample, psychiatrists indicate that about 25% of patients across allbipolar disorders are refractory during a manic episode, while about 70%are refractory during a depressive episode.

Accordingly, in various embodiments, the neurological or psychiatricdisease or disorder is one or more of bipolar depression, majordepressive episodes associated with bipolar I disorder, major depressivedisorder (MDD), persistent depressive disorder (Dysthymia), premenstrualdysphoric disorder (PMDD), major depressive disorder with mixed features(MDD-MF), depressive disorder due to another medical condition, otherspecified depressive disorder, unspecified depressive disorder, ortreatment resistant depression (TRD), and MDD with the specifiers ofanxious distress, with mixed features, with melancholic features, withatypical features, with mood-congruent psychotic features, withmood-incongruent psychotic features, with catatonia, with peripartumonset, and/or with seasonal pattern, and seasonal affective disorder.

It is to be understood that TRD is a term used in clinical psychiatry todescribe cases of major depressive disorder (MDD) that do not respondadequately to appropriate courses of adequate dose and duration of atleast two antidepressants.

In various embodiments, a depressive disorder is associated with acutesuicidality or suicide ideation. The United States Food and DrugAdministration has adopted a “black box” label warning indicating thatantidepressants may increase the risk of suicidal thinking and behaviorin some children, adolescents and young adults (up to age 24) with adepressive disorder such as MDD. In various embodiments, it is believedthat the compositions and methods of the present inventions do notincrease the risk of suicidal thinking and/or behavior in children,adolescents and/or young adults with a depressive disorder, e.g., withMDD. In various embodiments, the present inventions provide medicamentsfor and provide methods of treating one or more symptoms of a depressivedisorder (e.g., MDD) in children, adolescents and/or young adultswithout increasing the risk of suicidal thinking and/or behavior.

In various embodiments, the neurological or psychiatric disease ordisorder is schizophrenia. Schizophrenia is a disorder of unknownorigin, which usually appears for the first time in early adulthood andis marked by characteristics such as psychotic symptoms, phasicprogression and development, and/or deterioration in social behavior andprofessional capability. Characteristic psychotic symptoms are disordersof thought content (e.g., multiple, fragmentary, incoherent, implausibleor simply delusional contents, or ideas of persecution) and of mentality(e.g., loss of association, flight of imagination, incoherence up toincomprehensibility), as well as disorders of perceptibility (e.g.,hallucinations), emotions (e.g., superficial or inadequate emotions),self-perceptions, intentions, impulses, and/or inter-humanrelationships, and psychomotoric disorders (e.g., catatonia). Othersymptoms are also associated with this disorder. Schizophrenia isclassified into subgroups: the paranoid type, characterized by delusionsand hallucinations and absence of thought disorder, disorganizedbehavior, and affective flattening; the disorganized type, also named“hebephrenic schizophrenia,” in which thought disorder and flat affectare present together; the catatonic type, in which prominent psychomotordisturbances are evident, and symptoms may include catatonic stupor andwaxy flexibility; and the undifferentiated type, in which psychoticsymptoms are present but the criteria for paranoid, disorganized, orcatatonic types have not been met. The symptoms of schizophrenianormally manifest themselves in three broad categories: positive,negative and cognitive symptoms. Positive symptoms are those whichrepresent an “excess” of normal experiences, such as hallucinations anddelusions. Negative symptoms are those where the patient suffers from alack of normal experiences, such as anhedonia and lack of socialinteraction. The cognitive symptoms relate to cognitive impairment inschizophrenics, such as lack of sustained attention and deficits indecision making.

Accordingly, in various embodiments, the neurological or psychiatricdisease or disorder is one or more of schizotypal (personality)disorder, delusional disorder, brief psychotic disorder,schizophreniform disorder, schizophrenia, schizoaffective disorder,substance/medication-induced psychotic disorder, psychotic disorder dueto another medical condition, other specified schizophrenia spectrum andother psychotic disorder, unspecified schizophrenia spectrum, and otherpsychotic disorder.

It is to be understood that schizoaffective disorder includes acondition that includes aspects of both schizophrenia and a mooddisorder, such as, for example, a major depressive disorder, a bipolardisorder, major depressive episodes associated with a bipolar disorder,etc.

In various embodiments, the neurological or psychiatric disease ordisorder is anxiety disorder. Anxiety disorders are characterized byfear, worry, and uneasiness, usually generalized and unfocused as anoverreaction to a situation. Anxiety disorders differ in the situationsor types of objects that induce fear, anxiety, or avoidance behavior,and the associated cognitive ideation. Anxiety differs from fear in thatanxiety is an emotional response to a perceived future threat while fearis associated with a perceived or real immediate threat. They alsodiffer in the content of the associated thoughts or beliefs. Examples ofanxiety disorders include separation anxiety disorder, selective mutism,specific phobia, social anxiety disorder (social phobia), panicdisorder, panic attack specifier, agoraphobia, generalized anxietydisorder, substance/medication-induced anxiety disorder, anxietydisorder due to another medical condition, illness anxiety disorder,social (pragmatic) communication disorder, other specified anxietydisorder, and unspecified anxiety disorder; stressor-related disorders,including reactive attachment disorder, disinhibited social engagementdisorder, posttraumatic stress disorder (PTSD), acute stress disorder,and adjustment disorders.

In various embodiments, the neurological or psychiatric disease ordisorder is a sleep disorder including those sleep disorders which areproduced by psychiatric conditions, including, but not limited to,insomnia, disturbed sleep, jet lag, hypersomnia, cataplexy, sleeprelated disorder (e.g., sleep apnea, insomnia, narcolepsy, cataplexy),obstructive sleep apnea, REM sleep behavior disorder, Restless LegSyndrome, periodic limb movement disorder, circadian rhythm sleepdisorders, delayed sleep phase disorder, sleepwalking, night terrors,bed wetting, rapid eye movement sleep behavior disorder, shift worksleep disorder, excessive daytime sleepiness, non-24-hour sleep-wakedisorder, sleep paralysis and narcolepsy.

In various embodiments, the present inventions provide medicaments forand provide methods of suppressing rapid eye movement (REM) during bothsleep and daytime equivalent.

In various embodiments, the present inventions provide medicaments forand provide methods of suppressing or eliminating pathological orexcessive REM during the night or daytime equivalent.

In various embodiments, the neurological and/or psychiatric disease ordisorders are obsessive-compulsive disorder and related disorders (e.g.,body dysmorphic disorder, hoarding disorder, trichotillomania,excoriation disorder).

In various embodiments, the neurological and/or psychiatric diseases ordisorders are disruptive, impulse-control, and conduct disordersincluding oppositional defiant disorder, intermittent explosivedisorder, conduct disorder, antisocial personality disorder, pyromania,kleptomania, other specified disruptive, impulse-control, and conductdisorder, unspecified disruptive, impulse-control, and conduct disorder.

In various embodiments, the compositions, formulations, methods andmedicaments of the present inventions may be used in combination withother therapies. Suitable therapies include, but are not limited to,psychotherapy, cognitive behavioral therapy, electroconvulsive therapy,transcranial magnetic stimulation, vagus nerve stimulation, anddeep-brain stimulation.

In various aspects, the present inventions provide formulations andcompositions comprising unequal mixtures of amisulpride enantiomers (ora pharmaceutically acceptable salt of one or more of the enantiomers)and one or more pharmaceutically acceptable excipient, carrier,adjuvant, or vehicle.

It is to be understood, that in various embodiments the pharmaceuticalcompositions of the present inventions comprise one or morepharmaceutically acceptable excipients, including, but not limited to,one or more binders, bulking agents, buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, diluents, viscosityenhancing or reducing agents, emulsifiers, suspending agents,preservatives, antioxidants, opaquing agents, glidants, processing aids,colorants, sweeteners, taste-masking agents, perfuming agents, flavoringagents, diluents and other known additives to provide an elegantpresentation of the drug or aid in the manufacturing of a medicament orpharmaceutical product comprising a composition of the presentinventions. Examples of carriers and excipients well known to thoseskilled in the art and are described in detail in, e.g., Ansel, HowardC., et al., Ansel's Pharmaceutical Dosage Forms and Drug DeliverySystems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro,Alfonso R., et al. Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C.Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press,2005.

In various embodiments, the compositions are formulated with one or morepharmaceutically acceptable excipients in accordance with known andestablished practice. Thus, in various embodiments the composition areformulated as, for example, a liquid, powder, granules, elixir,injectable solution, or suspension. Formulations for oral use arepreferred and may be provided, for instance, as tablets, caplets, orcapsules, wherein the pharmacologically active ingredients are mixedwith an inert solid diluent. Tablets may also include granulating anddisintegrating agents, and may be coated or uncoated. Formulations fortopical use may be provided, for example as topical solutions, lotions,creams, ointments, gels, foams, patches, powders, solids, sponges,tapes, vapors, pastes or tinctures.

In various embodiments, the present inventions comprise compositionscomprising unequal mixtures of amisulpride enantiomers (or apharmaceutically acceptable salt of one or more of the enantiomers) andone or more pharmaceutically acceptable excipient, carrier, adjuvant, orvehicle, where the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is between about 25 mg and about 1000 mg, in variousembodiments between about 50 mg and about 750 mg, in various embodimentsbetween about 50 mg and about 300 mg and in various embodimentspreferably between about 100 mg and about 300 mg. In variousembodiments, such compositions comprise a ratio of (R)-(+)-amisulprideto (S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,that is in the range between about 80:20 to about 90:10 by weight offree base; and preferably in various embodiments the ratio is about85:15 by weight of free base.

In various embodiments, compositions comprising unequal mixtures ofamisulpride enantiomers formulated as a solid oral dosage form. It is tobe understood that the total amount of a composition of the comprisingan unequal mixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, need not be provided in asingle dosage unit forms, e.g. a single tablet, capsule, etc. In variousembodiments, it is preferred that the compositions be provided in dosageunit forms such that, for example, the administration of two of thedosage unit forms will result in administration of the desired combinedamount of (R)-amisulpride and (S)-amisulpride.

For example, in various embodiments provided are dosage unit formscomprising a total combined amount of (R)-amisulpride and(S)-amisulpride of about 100 mg (a 100 mg tablet/capsule), comprisingabout 85 mg (R)-amisulpride and about 15 mg (S)-amisulpride.Accordingly, administration of three of these 100 mg tablets/capsuleswould result in administration of a total combined amount of(R)-amisulpride and (S)-amisulpride of about 300 mg; whilstadministration of four of these 100 mg tablets/capsules would result inadministration of a total combined amount of (R)-amisulpride and(S)-amisulpride of about 400 mg.

For example, in various embodiments provided are dosage unit formscomprising a total combined amount of (R)-amisulpride and(S)-amisulpride of about 200 mg (a 200 mg tablet/capsule), comprisingabout 170 mg (R)-amisulpride and about 30 mg (S)-amisulpride.Accordingly, administration of two of these 200 mg tablets/capsuleswould result in administration of a total combined amount of(R)-amisulpride and (S)-amisulpride of about 400 mg; whilstadministration of three of these 200 mg tablets/capsules would result inadministration of a total combined amount of (R)-amisulpride and(S)-amisulpride of about 600 mg.

In various embodiments comprising an oral dosage form the dosage form isa liquid suspension or solution. For example, in various embodiments,the oral dosage form comprises an unequal mixture of (R)-(+)-amisulprideand (S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,dissolved or suspended in a liquid with one or more pharmaceuticallyacceptable excipients. In various embodiments, a liquid dosage formcomprises the total combined active ingredients ((R)-amisulpride and(S)-amisulpride) suspended or dissolved in 20 mL solution with a citratebuffer.

In various embodiments, the present inventions provide liquid oraldosage forms comprising a solution substantially in accord with that setforth in Table 1, where in Table 1 the “API mg per mL (R:S 85:15)”column indicates the total combined amount of (R)-amisulpride and(S)-amisulpride (where the ratio of (R)-amisulpride to (S)-amisulprideis 85:15 by weight) per mL of aqueous solution, the pH column indicatesthe buffered pH range, and the percentages are weight percent.

TABLE 1 API per mL (R:S 85:15) pH Sweetener(s) Buffer(s) Preservative(s)100 mg 3 to 5 50% glycerin 10 mM 0.2% sodium 0.5% sucralose citric acidbenzoate 33.3 mg 3 to 5 16.7% glycerin 10 mM 0.2% sodium 0.167%sucralose citric acid benzoate 10 mg 3 to 5 5% glycerin 10 mM 0.2%sodium 0.05% sucralose citric acid benzoate

In various embodiments, formulations of the present inventions suitablefor oral administration are provided as capsules, cachets or tabletseach containing a predetermined amount of the active pharmaceuticalingredients ((R)-amisulpride and (S)-amisulpride and pharmaceuticallyacceptable salts thereof) as a powder, granules or both, and one morepharmaceutically acceptable excipients.

In various embodiments, solid oral dosage forms of the presentinventions are in the form of a tablet comprising a core having: (a) atotal combined amount of (R)-amisulpride and (S)-amisulpriderepresenting between about 20% to about 40% of the total weight, wherethe tablet ratio of (R)-amisulpride to (S)-amisulpride is about 85:15 byweight of free base, (b) between about 30% and about 55% of a filler(e.g., one or more of mannitol, lactose monohydrate), and (c) betweenabout 15% and about 30% of disintegrant (e.g. a pregelatinzed starch,croscarmellose sodium). In various embodiments, the core furthercomprises: (i) between about 1% and about 5% of a binder (e.g. apolyvinyl alcohol, including but not limited to partially hydrolyzedpolyvinyl alcohols); and (ii) between about 0.75% and about 3% of alubricant (e.g. magnesium stearate).

In various embodiments, the present inventions provide solid oral dosageforms comprising a tablet having a core substantially in accord withthat set forth in Table 2. In various embodiments, the presentinventions provide solid oral dosage forms comprising a tablet having acore substantially in accord with that set forth in Table 2 and acoating substantially in accord with that set forth in Table 3, where inTables 2 and 3 the abbreviation q.s. means quantum sufficiat (as much asnecessary) and where it is to be understood that the purified water wasand is to be removed during processing.

TABLE 2 Core Composition Core 100 mg Tablet 200 mg Tablet ComponentFunction mg/tab % w/w mg/tab % w/w (R)- Drug 85 17.0 170 34.0amisulpride substance (S)- Drug 15 3.0 30 6.0 amisulpride substanceD-mannitol Filler 267.5 53.5 167.5 33.5 Pre- Filler 100 20.0 100 20.0gelatinized starch Polyvinyl Binder 10 2.0 10 2.0 alcohol Croscar- Dis-15 3.0 15 3.0 mellose integrant sodium Magnesium Lubricant 7.5 1.5 7.51.5 stearate Purified Granula- q.s. — q.s. — water tion solvent Subtotal500 100 500 100 (core)

TABLE 3 Film-Coat Composition Film-coat Quantity Component Function(mg/tab) Hydroxypropyl Coating agent 3.78 methylcellulose Macrogol 400Coating agent 0.38 Titanium dioxide Coating agent 1.89 Talc Coatingagent 1.36 Iron (III) oxide yellow Coloring agent 0.11 Iron (III) oxidered Coloring agent 0.05 Carnauba wax Polishing agent 0.01 Purified waterCoating solvent q.s. Subtotal (film) 7.58

In various embodiments, a tablet having a core substantially in accordwith Table 2 and a coating substantially in accord with Table 3 isprovided. In various preferred embodiments, all excipients comply withthe respective The United States Pharmacopeia (USP), The JapanesePharmacopoeia (JP), Japanese Pharmaceutical Excipients (JPE), TheEuropean Pharmacopoeia (Ph. Eur.), and/or The National Formulary (NF)monograph.

In various embodiments, the active pharmaceutical ingredients((R)-amisulpride and (S)-amisulpride and pharmaceutically acceptablesalts thereof) are provided as a dry powder blended with thepharmaceutically acceptable excipients. In various embodiments, theactive pharmaceutical ingredients ((R)-amisulpride and (S)-amisulprideand pharmaceutically acceptable salts thereof) are granules. In variousembodiments, one or both of the active pharmaceutical ingredients(R)-amisulpride and (S)-amisulpride are crystalline compounds,respectively, of Form A and Form A′.

In various embodiments of granulated active pharmaceutical ingredients,the granules are disposed in a capsule together with one morepharmaceutically acceptable excipients. In various embodiments, providedare capsules comprising granulated active pharmaceutical ingredientstogether with pharmaceutically acceptable excipients in amounts andproportions substantially in accord with those of Table 2. In variousembodiments of granulated active pharmaceutical ingredients the granulesare coated with a coating substantially in accord with the coatings ofTable 3.

In various embodiments, the pharmaceutical compositions and oral dosageforms are immediate release pharmaceutical compositions. In variousembodiments, the immediate release pharmaceutical compositions areformulated (for example, with respect to active ingredient amounts) tobe administered once, twice, three times or four times daily. In variousembodiments, the enantiomeric ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, ofthe composition is in the range between about 80:20 to about 90:10 byweight. In various embodiments, the ratio of (R)-amisulpride to(S)-amisulpride, or pharmaceutically acceptable salts thereof, by weightis about: 80:20, 81:19, 82:18, 83:17, 84:16, 85:15, 86:14, 87:13, 88:12,89:11, or 90:10. Preferably in various embodiments the ratio of(R)-amisulpride to (S)-amisulpride, or pharmaceutically acceptable saltsthereof, is 85:15 by weight. In various embodiments, the total combinedamount of (R)-amisulpride and (S)-amisulpride in an immediate releasepharmaceutical composition is about 50 mg, 75 mg, 100 mg, 150 mg, 200mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, or1000 mg. In various embodiments, once administered, or as administeredover a treatment cycle, the total combined amount of (R)-(+)-amisulprideand (S)-(−)-amisulpride ranges from about 50-1000 mg. In variousembodiments, once administered, or as administered over a treatmentcycle, the total combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride ranges from about 200-750 mg.

In various embodiments, the enantiomeric ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride over a treatment cycle is about 85:15 by weight, thetreatment cycle is daily and the total amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is 200 mg over the treatment cycle. In variousembodiments, the enantiomeric ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride over a treatment cycle is about 85:15 by weight, thetreatment cycle is daily and the total amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride is 400 mg over the treatment cycle.

In various the total combined amount of (R)-amisulpride and(S)-amisulpride in an immediate release pharmaceutical composition, onceadministered to a subject, or as administered to a subject over atreatment cycle, is sufficient to provide an occupancy of dopamine D2receptors between about 20% and about 60%; and a suppression of time inrapid eye movement (REM) sleep characterized, for example, by one ormore of: (a) a decrease in REM sleep by an amount greater than about 10minutes; (b) a latency to REM sleep by an amount greater than about 15minutes, or (c) a decrease in total REM sleep time relative to totalsleep time by an amount greater than about 5%. In various embodiments ofan immediate release composition, the total combined amount of(R)-amisulpride and (S)-amisulpride is sufficient to cause a suppressionof the time in rapid eye movement (REM) sleep by an amount between about15 minutes and about 60 minutes.

In various embodiments of an immediate release pharmaceuticalcomposition of the present invention, the immediate releasepharmaceutical composition further contains a carrier system thatincludes one or more excipients, including, but not limited to, abinder, a bulking agent, a buffer, a stabilizing agent, a surfactant, adisintegrant, a wetting agent, a lubricating agent, a diluent, aviscosity enhancing or reducing agent, an emulsifier, a suspendingagent, a preservatives, an opaquing agent, a glidant, a processing aid,a colorant, a sweetener, a taste-masking agent, a perfuming agent, or aflavoring agent. The amounts of any such excipient ingredients can bedetermined by those of ordinary skill in the art to maximize delivery ofthe (R)-amisulpride, the (S)-amisulpride, or both, to the site ofinterest.

In various embodiments, the oral dosage forms of the present inventionsmake use of a distinct polymorph of (R)-(+)-amisulpride,(S)-(−)-amisulpride referred to as Form A for the free base crystallineform of (R)-amisulpride, and Form A′ for the free base crystalline formof (S)-amisulpride, and described in further detail herein. In variousembodiments the enantiomeric amisulpride is provided in one or more ofhigh polymorph purity, chiral purity, and chemical purity.

In some embodiments, the present disclosure provides a pharmaceuticalcomposition comprising:

an amount between about 85 mg and about 600 mg of (R)-(+)-amisulpride,or a pharmaceutically acceptable salt thereof, by weight of free base;and

an amount between about 15 mg and about 100 mg (S)-(−)-amisulpride, or apharmaceutically acceptable salt thereof, by weight of free base;

in the enantiomeric ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpridebetween about 65:35 and about 88:12 by weight of free base.

In some embodiments, the ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride is between about 75:25 to about 88:12 by weight offree base. In some embodiments, the ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride is between about 80:20 to about 88:12 by weight offree base. In some embodiments, the ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride is between about 85:15 by weight of free base.

In some embodiments, the pharmaceutical composition comprises:

an amount between about 170 mg and about 340 mg of (R)-(+)-amisulpride,or a pharmaceutically acceptable salt thereof, by weight of free base;and

an amount between about 30 mg and about 60 mg (S)-(−)-amisulpride, or apharmaceutically acceptable salt thereof, by weight of free base.

In some embodiments, the pharmaceutical composition comprises:

an amount about 170 mg of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base; and

an amount about 30 mg of (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base.

In some embodiments, the pharmaceutical composition comprises:

an amount about 340 mg of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base; and

an amount about 60 mg of (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base.

In some embodiments, the combined amount of (R)-(+)-amisulpride, or apharmaceutically acceptable salt thereof, and (S)-(−)-amisulpride, or apharmaceutically acceptable salt thereof, is about 100 mg, 200 mg, 300mg, 400 mg, 500 mg, 600 mg or 700 mg by weight of free base. In someembodiments, the combined amount of (R)-(+)-amisulpride, or apharmaceutically acceptable salt thereof, and (S)-(−)-amisulpride, or apharmaceutically acceptable salt thereof, is between about 200 mg andabout 600 mg by weight of free base. In some embodiments, the combinedamount of (R)-(+)-amisulpride, or a pharmaceutically acceptable saltthereof, and (S)-(−)-amisulpride, or a pharmaceutically acceptable saltthereof, is between about 200 mg and about 400 mg by weight of freebase. In some embodiments, the combined amount of (R)-(+)-amisulpride,or a pharmaceutically acceptable salt thereof, and (S)-(−)-amisulpride,or a pharmaceutically acceptable salt thereof, is about 200 mg by weightof free base. In some embodiments, the combined amount of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, and(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof, isabout 400 mg by weight of free base.

In some embodiments, the (R)-(+)-amisulpride is crystalline(R)-(+)-amisulpride of crystal Form A; and the (S)-(−)-amisulpride iscrystalline (S)-(−)-amisulpride of crystal Form A′.

In some embodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, iseffective to provide in the subject after administration an occupancy ofdopamine D2 receptors between about 20% and about 60%. In someembodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, iseffective to provide in the subject after administration an occupancy ofdopamine D2 receptors between about 30% and about 50%.

In some embodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, iseffective to provide in the subject after administration a suppressionof the time in rapid eye movement (REM) sleep as characterized by adecrease in REM sleep by an amount greater than about 10 minutes. Insome embodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, iseffective to provide in the subject after administration a suppressionof the time in rapid eye movement (REM) sleep as characterized by adecrease in REM sleep by an amount between about 15 minutes and about 45minutes. In some embodiments, the combined amount of (R)-(+)-amisulprideand (S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,is effective to provide in the subject after administration asuppression of the time in rapid eye movement (REM) sleep ascharacterized by a decrease in REM sleep by an amount between about 15minutes and about 30 minutes. In some embodiments, the combined amountof (R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, is effective to provide in the subject afteradministration a suppression of the time in rapid eye movement (REM)sleep as characterized by a latency to REM sleep by an amount greaterthan about 20 minutes. In some embodiments, the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, is effective to provide in the subject afteradministration a suppression of the time in rapid eye movement (REM)sleep as characterized by a latency to REM sleep by an amount greaterthan about 30 minutes.

In some embodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,effective to provide in the subject after administration a suppressionof the time in rapid eye movement (REM) sleep as characterized by adecrease in total REM sleep time relative to total sleep time by anamount greater than about 5%. In some embodiments, the combined amountof (R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, effective to provide in the subject afteradministration a suppression of the time in rapid eye movement (REM)sleep as characterized by a decrease in total REM sleep time relative tototal sleep time by an amount greater than about 6.5%.

In some embodiments, the combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,effective to provide in the subject after administration:

an occupancy of dopamine D2 receptors between about 30% and about 50%;and a suppression of the time in rapid eye movement (REM) sleep by anamount between about 15 minutes and about 45 minutes.

In some embodiments, provided herein is a pharmaceutical compositioncomprising an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride, and wherein the amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride in the composition is effective to provide in asubject after administration:

-   -   an occupancy of dopamine D2 receptors between about 20% and        about 60%; and    -   a suppression of time in rapid eye movement (REM) sleep as        characterized by one or more of:    -   a decrease in REM sleep by an amount greater than about 10        minutes,    -   a latency to REM sleep by an amount greater than about 20        minutes, or    -   a decrease in total REM sleep time relative to total sleep time        by an amount greater than about 5%.        In some embodiments, the occupancy of dopamine D2 receptors is        between about 30% and about 50%. In some embodiments, the        decrease in REM sleep is between about 15 minutes and about 45        minutes. In some embodiments, the latency to REM sleep is by an        amount greater than about 30 minutes. In some embodiments, the        decrease in total REM sleep time relative to total sleep time is        by an amount greater than about 6.5%. In some embodiments, the        ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride is between        about 85:15 by weight of free base. In some embodiments, the        combined amount of (R)-(+)-amisulpride, or a pharmaceutically        acceptable salt thereof, and (S)-(−)-amisulpride, or a        pharmaceutically acceptable salt thereof, is between about 100        mg and about 700 mg by weight of free base.

In some embodiments, provided herein is a pharmaceutical compositioncomprising an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride, in amounts effective to provide in a subject afteradministration:

-   -   inhibition of dopamine D2 activity and serotonin 5-HT7 activity        in said subject such that the ratio of the serotonin 5-HT7        receptor inhibitory constant to the dopamine D2 receptor        inhibitory constant is in the range between about 2 to about 6.        In some embodiments, the ratio of the serotonin 5-HT7 receptor        inhibitory constant to the dopamine D2 receptor inhibitory        constant is in the range between about 3 to about 5. In some        embodiments, the ratio of the serotonin 5-HT7 receptor        inhibitory constant to the dopamine D2 receptor inhibitory        constant is about 4. In some embodiments, the dopamine D2        receptor inhibitory constant is in the range between about 11 nM        to about 20 nM and the serotonin 5-HT7 receptor inhibitory        constant is in the range between about 40 nM to about 85 nM. In        some embodiments, the dopamine D2 receptor inhibitory constant        is about 17 nM and the serotonin 5-HT7 receptor inhibitory        constant is about 66 nM.

In some embodiments, the composition is provided in a solid oral dosageform comprising one or more pharmaceutically acceptable excipients. Insome embodiments, the total combined amount of (R)-amisulpride and(S)-amisulpride comprises between about 20% to about 40% of the totalweight of the pharmaceutical composition; and the one or morepharmaceutically acceptable excipients comprise:

-   -   a filler comprising between about 30% and about 55% of the total        weight of the pharmaceutical composition; and    -   a disintegrant comprising between about 15% and about 30% of the        total weight of the pharmaceutical composition.

In some embodiments provided herein is a liquid pharmaceuticalcomposition comprising:

one or more pharmaceutically acceptable excipients; and

an aqueous solution comprising an unequal mixture of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, and(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof, witha combined amount between about 5 mg/mL and about 200 mg/mL, wherein theratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride is in the rangebetween about 65:35 to about 88:12 by weight of free base.

In some embodiments, this disclosure provides a method of treating apsychiatric disorder in a subject comprising administering apharmaceutical composition provided herein. In some embodiments, thepsychiatric disorder is a depressive disorder. In some embodiments, thepsychiatric disorder is major depressive disorder (MDD). In someembodiments, the psychiatric disorder is major depressive disorder withmixed features (MDD-MF). In some embodiments, the psychiatric disorderis treatment resistant depression (TRD). In some embodiments, thepsychiatric disorder is one or more of schizophrenia and negativesymptoms of schizophrenia. In some embodiments, the psychiatric disorderis schizoaffective disorder. In some embodiments, the psychiatricdisorder is bipolar disorder. In some embodiments, the psychiatricdisorder is bipolar depression. In some embodiments, the method oftreatment treats two or more of schizophrenia, negative symptoms ofschizophrenia, treatment resistant depression, bipolar disorder anddepression.

In some embodiments, the composition provided herein is administeredonce daily.

In some embodiments, provided herein is a method of inhibiting dopamineD2 activity and serotonin 5-HT7 activity in a subject, comprisingadministering to a subject an effective amount of an unequal mixture of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, and(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof.

In various embodiments, provided herein is a method of treating bipolardisorder comprising administering to a subject in need thereof aneffective amount of a composition comprising: an amount between about 85mg and about 600 mg of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base; and an amount betweenabout 15 mg and about 100 mg (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base; wherein theenantiomeric ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride in thecomposition is more than 50:50 by weight of free base.

In some embodiments, provided herein is a method of treating bipolardisorder comprising administering to a subject in need thereof aneffective amount of a composition comprising:

an amount between about 85 mg and about 600 mg of (R)-(+)-amisulpride,or a pharmaceutically acceptable salt thereof, by weight of free base;and

an amount between about 15 mg and about 100 mg (S)-(−)-amisulpride, or apharmaceutically acceptable salt thereof, by weight of free base;

wherein the enantiomeric ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride in the composition is between about 65:35 and about88:12 by weight of free base.

In some embodiments, the bipolar disorder is bipolar depression.

In some embodiments, provided herein is a method of treating bipolardepression comprising administering once daily to a subject in needthereof an effective amount of a composition comprising:

an amount about 170 mg of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base; and

an amount about 30 mg of (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base.

In some embodiments, provided herein is a method of treating bipolardepression comprising administering once daily to a subject in needthereof an effective amount of a composition comprising:

an amount about 340 mg of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base; and

an amount about 60 mg of (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base.

The present disclosure also provides the following embodiments:

Embodiment 1

A pharmaceutical composition comprising an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, wherein the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride, wherein said unequalmixture is effective to provide in a subject after administration:

-   -   an occupancy of dopamine D2 receptors between about 20% and        about 60%; and    -   a suppression of time in rapid eye movement (REM) sleep as        characterized by one or more of:    -   a decrease in REM sleep by an amount greater than about 10        minutes,    -   a latency to REM sleep by an amount greater than about 20        minutes, or    -   a decrease in total REM sleep time relative to total sleep time        by an amount greater than about 5%.

Embodiment 2

The pharmaceutical composition of embodiment 1, wherein the occupancy ofdopamine D2 receptors is between about 30% and about 50%.

Embodiment 3

The pharmaceutical composition of embodiment 1, wherein the decrease inREM sleep is between about 15 minutes and about 45 minutes.

Embodiment 4

The pharmaceutical composition of embodiment 1, wherein the latency toREM sleep is by an amount greater than about 30 minutes.

Embodiment 5

The pharmaceutical composition of embodiment 1, wherein the decrease intotal REM sleep time relative to total sleep time is by an amountgreater than about 6.5%.

Embodiment 6

The pharmaceutical composition of embodiment 1, wherein the ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is in the range between about80:20 to about 90:10 by weight.

Embodiment 7

The pharmaceutical composition of embodiment 6, wherein the ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is 85:15 by weight.

Embodiment 8

The pharmaceutical composition of embodiment 1, wherein the(R)-(+)-amisulpride is crystalline (R)-(+)-amisulpride of crystal FormA; and the (S)-(−)-amisulpride is crystalline

(S)-(−)-amisulpride of crystal Form A′.

Embodiment 9

The pharmaceutical composition of embodiment 1, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about50 mg and about 1000 mg.

Embodiment 10

The pharmaceutical composition of embodiment 1, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about200 mg and about 700 mg.

Embodiment 11

The pharmaceutical composition of embodiment 1, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg.

Embodiment 12

The pharmaceutical composition of embodiment 1, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 500 mg.

Embodiment 13

The pharmaceutical composition of embodiment 1, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg.

Embodiment 14

The pharmaceutical composition of embodiment 1, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg.

Embodiment 15

The pharmaceutical composition of embodiment 1, wherein the compositionis provided in a solid oral dosage form comprising one or morepharmaceutically acceptable excipients.

Embodiment 16

A pharmaceutical composition comprising an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, wherein the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride, in amounts effective toprovide in a subject after administration:

-   -   inhibition of dopamine D2 activity and serotonin 5-HT7 activity        in said subject such that the ratio of the serotonin 5-HT7        receptor inhibitory constant to the dopamine D2 receptor        inhibitory constant is in the range between about 2 to about 6.

Embodiment 17

The pharmaceutical composition of embodiment 16, wherein the ratio ofthe serotonin 5-HT7 receptor inhibitory constant to the dopamine D2receptor inhibitory constant is in the range between about 3 to about 5.

Embodiment 18

The pharmaceutical composition of embodiment 17, wherein the ratio ofthe serotonin 5-HT7 receptor inhibitory constant to the dopamine D2receptor inhibitory constant is about 4.

Embodiment 19

The pharmaceutical composition of embodiment 16, wherein the dopamine D2receptor inhibitory constant is in the range between about 11 nM toabout 20 nM and the serotonin 5-HT7 receptor inhibitory constant is inthe range between about 40 nM to about 85 nM.

Embodiment 20

The pharmaceutical composition of embodiment 19, wherein the dopamine D2receptor inhibitory constant is about 17 nM and the serotonin 5-HT7receptor inhibitory constant is about 66 nM.

Embodiment 21

The pharmaceutical composition of embodiment 16, wherein the ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is in the range between about80:20 to about 90:10 by weight.

Embodiment 22

The pharmaceutical composition of embodiment 21, wherein the ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is 85:15 by weight.

Embodiment 23

The pharmaceutical composition of embodiment 16, wherein the(R)-(+)-amisulpride is crystalline (R)-(+)-amisulpride of crystal FormA; and the (S)-(−)-amisulpride is crystalline

(S)-(−)-amisulpride of crystal Form A′.

Embodiment 24

The pharmaceutical composition of embodiment 16, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about50 mg and about 1000 mg.

Embodiment 25

The pharmaceutical composition of embodiment 16, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about200 mg and about 700 mg.

Embodiment 26

The pharmaceutical composition of embodiment 16, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg.

Embodiment 27

The pharmaceutical composition of embodiment 16, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 500 mg.

Embodiment 28

The pharmaceutical composition of embodiment 16, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg.

Embodiment 29

The pharmaceutical composition of embodiment 16, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg.

Embodiment 30

The pharmaceutical composition of embodiment 16, wherein the unequalmixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride, or saltsthereof, are in amounts effective to provide in a subject afteradministration:

-   -   an occupancy of dopamine D2 receptors between about 30% and        about 50%; and    -   a suppression of the time in rapid eye movement (REM) sleep by        an amount between about 15 minutes and about 45 minutes.

Embodiment 31

The pharmaceutical composition of embodiment 30, wherein the(R)-(+)-amisulpride is present in an amount between about 300 mg toabout 600 mg and the (S)-(−)-amisulpride is present in an amount betweenabout 40 mg to about 105 mg.

Embodiment 32

The pharmaceutical composition of embodiment 16, wherein the compositionis provided in a solid oral dosage form comprising one or morepharmaceutically acceptable excipients.

Embodiment 33

A pharmaceutical composition comprising:

a pharmaceutically acceptable excipient; and

a combined amount of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, and (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, between about 50 mg and about 1000 mg, in theenantiomeric ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride ofabout 85:15 by weight.

Embodiment 34

The pharmaceutical composition of embodiment 33, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about200 mg and about 700 mg.

Embodiment 35

The pharmaceutical composition of embodiment 33, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg.

Embodiment 36

The pharmaceutical composition of embodiment 33, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 500 mg.

Embodiment 37

The pharmaceutical composition of embodiment 33, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg.

Embodiment 38

The pharmaceutical composition of embodiment 33, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg.

Embodiment 39

The pharmaceutical composition of embodiment 33, wherein the(R)-(+)-amisulpride is crystalline (R)-(+)-amisulpride of crystal FormA; and the (S)-(−)-amisulpride is crystalline

(S)-(−)-amisulpride of crystal Form A′.

Embodiment 40

The pharmaceutical composition of embodiment 33 wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is effective toprovide in a subject after administration:

-   -   an occupancy of dopamine D2 receptors is between about 20% and        about 60%; and    -   a suppression of the time in rapid eye movement (REM) sleep as        characterized by one or more of:    -   a decrease in REM sleep by an amount greater than about 10        minutes,    -   a latency to REM sleep by an amount greater than about 20        minutes, or    -   a decrease in total REM sleep time relative to total sleep time        by an amount greater than about 5%.

Embodiment 41

The pharmaceutical composition of embodiment 40, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is effective toprovide in a subject after administration:

-   -   an occupancy of dopamine D2 receptors between about 30% and        about 50%; and    -   a suppression of the time in rapid eye movement (REM) sleep by        an amount between about 15 minutes and about 45 minutes.

Embodiment 42

The pharmaceutical composition of embodiment 33, wherein the compositionis provided in a solid oral dosage form comprising one or morepharmaceutically acceptable excipients.

Embodiment 43

A pharmaceutical composition comprising:

a pharmaceutically acceptable excipient; and

an unequal mixture of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, and (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, in a combined amount between about 50 mg andabout 1000 mg, wherein the amount of (R)-(+)-amisulpride is greater thanthe amount of (S)-(−)-amisulpride and wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is present an amounteffective to provide in a subject after administration:

an occupancy of dopamine D2 receptors between about 20% and about 60%;and

a suppression of the time in rapid eye movement (REM) sleep ascharacterized by a decrease in REM sleep by an amount greater than about10 minutes.

Embodiment 44

The pharmaceutical composition of embodiment 43, wherein the ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is in the range between about80:20 to about 90:10 by weight.

Embodiment 45

The pharmaceutical composition of embodiment 43, wherein the ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is 85:15 by weight.

Embodiment 46

The pharmaceutical composition of embodiment 43, wherein the occupancyof dopamine D2 receptors is between about 30% and about 50%.

Embodiment 47

The pharmaceutical composition of embodiment 43, wherein the decrease inREM sleep is between about 15 minutes and about 45 minutes.

Embodiment 48

The pharmaceutical composition of embodiment 43, wherein the(R)-(+)-amisulpride is crystalline (R)-(+)-amisulpride of crystal FormA; and the (S)-(−)-amisulpride is crystalline

(S)-(−)-amisulpride of crystal Form A′.

Embodiment 49

The pharmaceutical composition of embodiment 43, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about200 mg and about 700 mg.

Embodiment 50

The pharmaceutical composition of embodiment 43, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg.

Embodiment 51

The pharmaceutical composition of embodiment 43, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 500 mg.

Embodiment 52

The pharmaceutical composition of embodiment 43, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg.

Embodiment 53

The pharmaceutical composition of embodiment 43, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg.

Embodiment 54

A method of treating a psychiatric disorder in a subject comprisingadministering a pharmaceutical composition comprising an unequal mixtureof (R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, wherein the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride, wherein said unequalmixture is administered in a therapeutically effective amount to providein a subject after administration:

-   -   an occupancy of dopamine D2 receptors between about 20% and        about 60%; and    -   a suppression of the time in rapid eye movement (REM) sleep as        characterized by one or more of:    -   a decrease in REM sleep by an amount greater than about 10        minutes,    -   a latency to REM sleep by an amount greater than about 20        minutes, or    -   a decrease in total REM sleep time relative to total sleep time        by an amount greater than about 5%.

Embodiment 55

The method of embodiment 54 wherein the psychiatric disorder is adepressive disorder.

Embodiment 56

The method of embodiment 55 wherein the psychiatric disorder is majordepressive disorder (MDD).

Embodiment 57

The method of embodiment 54 wherein the psychiatric disorder is majordepressive disorder with mixed features (MDD-MF).

Embodiment 58

The method of embodiment 54 wherein the psychiatric disorder istreatment resistant depression (TRD).

Embodiment 59

The method of embodiment 54 wherein the psychiatric disorder is one ormore of schizophrenia and negative symptoms of schizophrenia.

Embodiment 60

The method of embodiment 54 wherein the psychiatric disorder isschizoaffective disorder.

Embodiment 61

The method of embodiment 54 wherein the psychiatric disorder is bipolardisorder.

Embodiment 62

The method of embodiment 54 wherein the psychiatric disorder is bipolardepression.

Embodiment 63

The method of embodiment 54 wherein method of treatment treats two ormore of schizophrenia, negative symptoms of schizophrenia, treatmentresistant depression, bipolar disorder and depression.

Embodiment 64

The method of embodiment 54, wherein the occupancy of dopamine D2receptors is between about 30% and about 50%.

Embodiment 65

The method of embodiment 54, wherein the decrease in REM sleep isbetween about 15 minutes and about 45 minutes.

Embodiment 66

The method of embodiment 54, wherein the decrease in REM sleep isbetween about 15 minutes and about 30 minutes.

Embodiment 67

The method of embodiment 54, wherein the decrease in total REM sleeptime relative to total sleep time is by an amount greater than about6.5%.

Embodiment 68

The method of embodiment 54, wherein the ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride is in the range between about 80:20 to about 90:10by weight.

Embodiment 69

The method of embodiment 68, wherein the ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride is 85:15 by weight.

Embodiment 70

The method of embodiment 54, wherein the (R)-(+)-amisulpride iscrystalline (R)-(+)-amisulpride of crystal Form A; and the(S)-(−)-amisulpride is crystalline

(S)-(−)-amisulpride of crystal Form A′.

Embodiment 71

The method of embodiment 54, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 50 mg andabout 1000 mg.

Embodiment 72

The method of embodiment 54, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 200 mg andabout 700 mg.

Embodiment 73

The method of embodiment 54, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg.

Embodiment 74

The method of embodiment 54, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 500 mg.

Embodiment 75

The method of embodiment 54, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg.

Embodiment 76

The method of embodiment 54, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg.

Embodiment 77

The method of embodiment 54, wherein the composition is provided in asolid oral dosage form comprising one or more pharmaceuticallyacceptable excipients.

Embodiment 78

A method of treating a psychiatric disorder in a subject comprisingadministering an unequal mixture of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride, in therapeutically effective amounts to provide ina subject after administration:

-   -   inhibition of dopamine D2 activity and serotonin 5-HT7 activity        in said subject such that the ratio of the serotonin 5-HT7        receptor inhibitory constant to the dopamine D2 receptor        inhibitory constant is in the range between about 2 to about 6.

Embodiment 79

The method of embodiment 78 wherein the psychiatric disorder is adepressive disorder.

Embodiment 80

The method of embodiment 79 wherein the psychiatric disorder is majordepressive disorder (MDD).

Embodiment 81

The method of embodiment 78 wherein the psychiatric disorder is majordepressive disorder with mixed features (MDD-MF).

Embodiment 82

The method of embodiment 78 wherein the psychiatric disorder istreatment resistant depression (TRD).

Embodiment 83

The method of embodiment 78 wherein the psychiatric disorder is one ormore of schizophrenia and negative symptoms of schizophrenia.

Embodiment 84

The method of embodiment 78 wherein the psychiatric disorder isschizoaffective disorder.

Embodiment 85

The method of embodiment 78 wherein the psychiatric disorder is bipolardisorder.

Embodiment 86

The method of embodiment 78 wherein the psychiatric disorder is bipolardepression

Embodiment 87

The method of embodiment 78 wherein method of treatment treats two ormore of schizophrenia, negative symptoms of schizophrenia, treatmentresistant depression, bipolar disorder and depression.

Embodiment 88

The method of embodiment 78, wherein the ratio of the serotonin 5-HT7receptor inhibitory constant to the dopamine D2 receptor inhibitoryconstant is about 4.

Embodiment 89

The method of embodiment 78, wherein the dopamine D2 receptor inhibitoryconstant is in the range between about 11 nM to about 20 nM and theserotonin 5-HT7 receptor inhibitory constant is in the range betweenabout 40 nM to about 60 nM.

Embodiment 90

The method of embodiment 89, wherein the dopamine D2 receptor inhibitoryconstant is about 17 nM and the serotonin 5-HT7 receptor inhibitoryconstant is about 66 nM.

Embodiment 91

The method of embodiment 78, wherein the ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride is in the range between about 80:20 to about 90:10by weight.

Embodiment 92

The method of embodiment 78, wherein the ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride is 85:15 by weight.

Embodiment 93

The method of embodiment 78, wherein the (R)-(+)-amisulpride iscrystalline (R)-(+)-amisulpride of crystal Form A; and the(S)-(−)-amisulpride is crystalline

(S)-(−)-amisulpride of crystal Form A′.

Embodiment 94

The method of embodiment 78, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 50 mg andabout 1000 mg.

Embodiment 95

The pharmaceutical composition of embodiment 78, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about200 mg and about 700 mg.

Embodiment 96

The method of embodiment 78, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg.

Embodiment 97

The method of embodiment 78, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 500 mg.

Embodiment 98

The method of embodiment 78, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg.

Embodiment 99

The method of embodiment 78, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg.

Embodiment 100

The method of embodiment 78, wherein the unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or salts thereof, are inamounts effective to provide in a subject after administration:

-   -   an occupancy of dopamine D2 receptors between about 30% and        about 50%; and    -   a suppression of the time in rapid eye movement (REM) sleep by        an amount between about 15 minutes and about 45 minutes.

Embodiment 101

The method of embodiment 100, wherein the (R)-(+)-amisulpride is presentin an amount between about 300 mg to about 600 mg and the(S)-(−)-amisulpride is present in an amount between about 40 mg to about100 mg.

Embodiment 102

The method of embodiment 78, wherein the composition is provided in asolid oral dosage form comprising one or more pharmaceuticallyacceptable excipients.

Embodiment 103

A method of treating a psychiatric disorder in a subject comprisingadministering a pharmaceutical composition comprising:

a pharmaceutically acceptable excipient; and

a combined amount of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, and (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, between about 400 mg and about 700 mg, in theenantiomeric ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride ofabout 85:15 by weight.

Embodiment 104

The method of embodiment 103 wherein the psychiatric disorder is adepressive disorder.

Embodiment 105

The method of embodiment 104 wherein the psychiatric disorder is majordepressive disorder (MDD).

Embodiment 106

The method of embodiment 103 wherein the psychiatric disorder is majordepressive disorder with mixed features (MDD-MF).

Embodiment 107

The method of embodiment 103 wherein the psychiatric disorder istreatment resistant depression (TRD).

Embodiment 108

The method of embodiment 103 wherein the psychiatric disorder is one ormore of schizophrenia and negative symptoms of schizophrenia.

Embodiment 109

The method of embodiment 103 wherein the psychiatric disorder isschizoaffective disorder.

Embodiment 110

The method of embodiment 103 wherein the psychiatric disorder is bipolardisorder.

Embodiment 111

The method of embodiment 103 wherein the psychiatric disorder is bipolardepression.

Embodiment 112

The method of embodiment 103 wherein method of treatment treats two ormore of schizophrenia, negative symptoms of schizophrenia, treatmentresistant depression, bipolar disorder and depression.

Embodiment 113

The method of embodiment 101, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 50 mg andabout 1000 mg.

Embodiment 114

The method of embodiment 103, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 200 mg andabout 700 mg.

Embodiment 115

The method of embodiment 103, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg.

Embodiment 116

The method of embodiment 103, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 500 mg.

Embodiment 117

The method of embodiment 103, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg.

Embodiment 118

The method of embodiment 103, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg.

Embodiment 119

The method of embodiment 103, wherein the (R)-(+)-amisulpride iscrystalline (R)-(+)-amisulpride of crystal Form A; and the(S)-(−)-amisulpride is crystalline

(S)-(−)-amisulpride of crystal Form A′.

Embodiment 120

The method of embodiment 103, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is effective to provide in asubject after administration:

-   -   an occupancy of dopamine D2 receptors is between about 20% and        about 60%; and    -   a suppression of the time in rapid eye movement (REM) sleep as        characterized by one or more of:    -   a decrease in REM sleep by an amount greater than about 10        minutes,    -   a latency to REM sleep by an amount greater than about 20        minutes, or    -   a decrease in total REM sleep time relative to total sleep time        by an amount greater than about 5%.

Embodiment 121

The method of embodiment 120, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is effective to provide in asubject after administration:

-   -   an occupancy of dopamine D2 receptors between about 30% and        about 50%; and    -   a suppression of the time in rapid eye movement (REM) sleep by        an amount between about 15 minutes and about 45 minutes.

Embodiment 122

The method of embodiment 103, wherein the composition is provided in asolid oral dosage form comprising one or more pharmaceuticallyacceptable excipients.

Embodiment 123

A method of treating a psychiatric disorder in a subject comprisingadministering a pharmaceutical composition comprising:

a pharmaceutically acceptable excipient; and

an unequal mixture of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, and (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, in a combined amount between about 50 mg andabout 1000 mg, wherein the amount of (R)-(+)-amisulpride is greater thanthe amount of (S)-(−)-amisulpride and wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is present an amounteffective to provide in a subject after administration:

-   -   an occupancy of dopamine D2 receptors between about 20% and        about 60%; and    -   a suppression of the time in rapid eye movement (REM) sleep as        characterized by a decrease in REM sleep by an amount greater        than about 10 minutes.

Embodiment 124

The method of embodiment 123 wherein the psychiatric disorder is adepressive disorder.

Embodiment 125

The method of embodiment 124 wherein the psychiatric disorder is majordepressive disorder (MDD).

Embodiment 126

The method of embodiment 123 wherein the psychiatric disorder istreatment resistant depression (TRD).

Embodiment 127

The method of embodiment 123 wherein the psychiatric disorder is one ormore of schizophrenia and negative symptoms of schizophrenia.

Embodiment 128

The method of embodiment 123 wherein the psychiatric disorder is majordepressive disorder with mixed features (MDD-MF).

Embodiment 129

The method of embodiment 123 wherein the psychiatric disorder isschizoaffective disorder.

Embodiment 130

The method of embodiment 123 wherein the psychiatric disorder is bipolardisorder.

Embodiment 131

The method of embodiment 123 wherein the psychiatric disorder is bipolardepression

Embodiment 132

The method of embodiment 123 wherein method of treatment treats two ormore of schizophrenia, negative symptoms of schizophrenia, treatmentresistant depression, bipolar disorder and depression.

Embodiment 133

The method of embodiment 123, wherein the ratio of (R)-(+)-amisulprideto (S)-(−)-amisulpride is in the range between about 80:20 to about90:10 by weight.

Embodiment 134

The method of embodiment 123, wherein the ratio of (R)-(+)-amisulprideto (S)-(−)-amisulpride is 85:15 by weight.

Embodiment 135

The method of embodiment 123, wherein the occupancy of dopamine D2receptors is between about 30% and about 50%.

Embodiment 136

The method of embodiment 123, wherein the decrease in REM sleep isbetween about 15 minutes and about 45 minutes.

Embodiment 137

The method of embodiment 123, wherein the (R)-(+)-amisulpride iscrystalline (R)-(+)-amisulpride of crystal Form A; and the(S)-(−)-amisulpride is crystalline

(S)-(−)-amisulpride of crystal Form A′.

Embodiment 138

The pharmaceutical composition of embodiment 123, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about200 mg and about 700 mg.

Embodiment 139

The method of embodiment 123, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg.

Embodiment 140

The method of embodiment 123, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 500 mg.

Embodiment 141

The method of embodiment 123, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg.

Embodiment 142

The method of embodiment 123, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg.

Embodiment 143

The method of embodiment 123, wherein the composition is provided in asolid oral dosage form.

Embodiment 144

A method of inhibiting dopamine D2 activity and serotonin 5-HT7 activityin a subject, comprising administering to a subject an effective amountof an unequal mixture of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, and (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof.

Embodiment 145

The method of embodiment 144 wherein the subject is a mammal.

Embodiment 146

The method of embodiment 145 wherein the subject is a human.

Embodiment 147

The method of embodiment 146 wherein the inhibition of dopamine D2activity and the inhibition serotonin 5-HT7 activity comprises:

-   -   an occupancy of dopamine D2 receptors between about 20% and        about 60%; and    -   a suppression of the time in rapid eye movement (REM) sleep as        characterized by one or more of:        -   a decrease in REM sleep by an amount greater than about 10            minutes,        -   a latency to REM sleep by an amount greater than about 20            minutes, or        -   a decrease in total REM sleep time relative to total sleep            time by an amount greater than about 5%.

Embodiment 148

The method of embodiment 146 wherein the inhibition takes place in asubject suffering from one or more psychiatric disorders.

Embodiment 149

The method of embodiment 148 wherein the psychiatric disorder is adepressive disorder.

Embodiment 150

The method of embodiment 149 wherein the psychiatric disorder is majordepressive disorder (MDD).

Embodiment 151

The method of embodiment 148 wherein the psychiatric disorder istreatment resistant depression (TRD).

Embodiment 152

The method of embodiment 148 wherein the psychiatric disorder is one ormore of schizophrenia and negative symptoms of schizophrenia.

Embodiment 153

The method of embodiment 148 wherein the psychiatric disorder is majordepressive disorder with mixed features (MDD-MF).

Embodiment 154

The method of embodiment 148 wherein the psychiatric disorder isschizoaffective disorder.

Embodiment 155

The method of embodiment 148 wherein the psychiatric disorder is bipolardisorder.

Embodiment 156

The method of embodiment 148 wherein the psychiatric disorder is bipolardepression.

Embodiment 157

The method of embodiment 148 wherein the psychiatric disorders comprisetwo or more of schizophrenia, negative symptoms of schizophrenia,treatment resistant depression, bipolar disorder and depression.

Embodiment 158

The method of embodiment 147 or 148 wherein the effective amount of anunequal mixture of (R)-(+)-amisulpride, or a salt thereof, and(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof is atherapeutically effective amount.

Embodiment 159

The method of embodiment 158 wherein the unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride comprises: an unequalmixture of (R)-(+)-amisulpride, or a pharmaceutically acceptable saltthereof, and (S)-(−)-amisulpride, or a pharmaceutically acceptable saltthereof, in a combined amount between about 50 mg and about 1000 mg,wherein the amount of (R)-(+)-amisulpride is greater than the amount of(S)-(−)-amisulpride.

Embodiment 160

The method of embodiment 159, wherein the combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride is between about 200 mg andabout 700 mg.

Embodiment 161

The method of embodiment 159 or embodiment 160 wherein the enantiomericratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride is about 85:15 byweight.

Embodiment 162

A method of treating a psychiatric disorder in a human subject,comprising administering on a treatment cycle an amount of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, andan amount of (S)-(−)-amisulpride, or a pharmaceutically acceptable saltthereof, in a combined amount between about 100 mg and about 1000 mg pertreatment cycle to a human subject in need thereof, wherein the amountof (R)-(+)-amisulpride is greater than the amount of (S)-(−)-amisulprideduring the treatment cycle.

Embodiment 163

The method of embodiment 162 wherein the treatment cycle is daily.

Embodiment 164

The method of embodiment 163 wherein an amount of (R)-(+)-amisulpride,or a pharmaceutically acceptable salt thereof, and an amount of(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof, areprovided once per day.

Embodiment 165

The method of embodiment 163 wherein an amount of (R)-(+)-amisulpride,or a pharmaceutically acceptable salt thereof, and an amount of(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof, areprovided about once every twelve hours.

Embodiment 166

The method of embodiment 162 wherein the treatment cycle is every twodays.

Embodiment 167

The method of embodiment 162 wherein the (R)-(+)-amisulpride, or apharmaceutically acceptable salt thereof, and the (S)-(−)-amisulpride,or a pharmaceutically acceptable salt thereof, are given separatelyduring a treatment cycle.

Embodiment 168

The method of embodiment 162 wherein the enantiomeric ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride over a treatment cycle isabout 85:15 by weight.

Embodiment 169

The method of embodiment 162 wherein the psychiatric disorder is adepressive disorder.

Embodiment 170

The method of embodiment 169 wherein the psychiatric disorder is majordepressive disorder (MDD).

Embodiment 171

The method of embodiment 162 wherein the psychiatric disorder istreatment resistant depression (TRD).

Embodiment 172

The method of embodiment 162 wherein the psychiatric disorder is one ormore of schizophrenia and negative symptoms of schizophrenia.

Embodiment 173

The method of embodiment 162 wherein the psychiatric disorder is majordepressive disorder with mixed features (MDD-MF).

Embodiment 174

The method of embodiment 162 wherein the psychiatric disorder isschizoaffective disorder.

Embodiment 175

The method of embodiment 162 wherein the psychiatric disorder is bipolardisorder.

Embodiment 176

The method of embodiment 162 wherein the psychiatric disorder is bipolardepression.

Embodiment 177

The method of embodiment 162 wherein the psychiatric disorder comprisestwo or more of schizophrenia, negative symptoms of schizophrenia,treatment resistant depression, bipolar disorder and depression.

Embodiment 178

A pharmaceutical composition comprising:

one or more pharmaceutically acceptable excipients; and

an unequal mixture of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, and (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, in a combined amount between about 50 mg andabout 1000 mg, wherein the ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride is in the range between about 80:20 to about 90:10by weight.

Embodiment 179

The pharmaceutical composition of embodiment 178, wherein the ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is 85:15 by weight.

Embodiment 180

The pharmaceutical composition of embodiment 178, wherein

the total combined amount of (R)-amisulpride and (S)-amisulpridecomprises between about 20% to about 40% of the total weight of thepharmaceutical composition; and

the one or more pharmaceutically acceptable excipients comprise:

a filler comprising between about 30% and about 55% of the total weightof the pharmaceutical composition; and

a disintegrant comprising between about 15% and about 30% of the totalweight of the pharmaceutical composition.

Embodiment 181

The pharmaceutical composition of embodiment 180, wherein the filler isD-mannitol.

Embodiment 182

The pharmaceutical composition of embodiment 181, wherein thedisintegrant is one or more of pregelatinzed starch and croscarmellosesodium.

Embodiment 183

The pharmaceutical composition of embodiment 181, further comprising:

a binder comprising between about 1% and about 3% of the total weight ofthe pharmaceutical composition; and

a lubricant comprising between about 0.75% and about 3% of the totalweight of the pharmaceutical composition.

Embodiment 184

The pharmaceutical composition of embodiment 178 where thepharmaceutical composition comprises a core comprised of the compositionof embodiment 178 and a coating about the core.

Embodiment 185

The pharmaceutical composition of embodiment 179 where thepharmaceutical composition comprises a core comprised of the compositionof embodiment 179 and a coating about the core.

Embodiment 186

The pharmaceutical composition of embodiment 180 where thepharmaceutical composition comprises a core comprised of the compositionof embodiment 180 and a coating about the core.

Embodiment 187

The pharmaceutical composition of embodiment 184, 185 or 186, whereinthe coating comprises a film coat comprised of one or more ofhydroxypropylmethylcellulose and talc.

Embodiment 188

A liquid pharmaceutical composition comprising:

one or more pharmaceutically acceptable excipients; and

an aqueous solution comprising an unequal mixture of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, and(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof, witha combined amount between about 5 mg/mL and about 200 mg/mL, wherein theratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride is in the rangebetween about 80:20 to about 90:10 by weight.

Embodiment 189

The pharmaceutical composition of embodiment 188, wherein the ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is 85:15 by weight.

Embodiment 190

The pharmaceutical composition of embodiment 188, further comprising

a buffer; and

a sweetener comprising between about 2% and about 60% of the totalweight of the aqueous solution.

Embodiment 191

The pharmaceutical composition of embodiment 190, wherein the sweetenercomprises one or more of glycerin and sucralose.

Embodiment 192

The pharmaceutical composition of embodiment 190, wherein the buffercomprises citric acid.

Embodiment 193

The pharmaceutical composition of embodiment 192, wherein the buffercomprises citric acid in an amount sufficient to maintain the pH of theaqueous solution between 3 to 5.

Embodiment 194

The pharmaceutical composition of embodiment 190, further comprising apreservative.

Embodiment 195

A pharmaceutical composition comprising an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, wherein the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride, in amounts effective toprovide in vitro:

inhibition of dopamine D2 activity and serotonin 5-HT7 activity in vitrosuch that the ratio of the serotonin 5-HT7 receptor inhibitory constantto the dopamine D2 receptor inhibitory constant is in the range betweenabout 2 to about 6.

Embodiment 196

The pharmaceutical composition of embodiment 195, wherein the ratio ofthe serotonin 5-HT7 receptor inhibitory constant to the dopamine D2receptor inhibitory constant is in the range between about 3 to about 5.

Embodiment 197

The pharmaceutical composition of embodiment 196, wherein the ratio ofthe serotonin 5-HT7 receptor inhibitory constant to the dopamine D2receptor inhibitory constant is about 4.

Embodiment 198

The pharmaceutical composition of embodiment 195, wherein the dopamineD2 receptor inhibitory constant is in the range between about 11 nM toabout 20 nM and the serotonin 5-HT7 receptor inhibitory constant is inthe range between about 40 nM to about 85 nM.

Embodiment 199

The pharmaceutical composition of embodiment 198, wherein the dopamineD2 receptor inhibitory constant is about 17 nM and the serotonin 5-HT7receptor inhibitory constant is about 66 nM.

Embodiment 200

The pharmaceutical composition of embodiment 195, wherein the ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is in the range between about80:20 to about 90:10 by weight.

Embodiment 201

The pharmaceutical composition of embodiment 200, wherein the ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is 85:15 by weight.

Embodiment 202

The pharmaceutical composition of embodiment 195, wherein the(R)-(+)-amisulpride is crystalline (R)-(+)-amisulpride of crystal FormA; and the (S)-(−)-amisulpride is crystalline

(S)-(−)-amisulpride of crystal Form A′.

Embodiment 203

The pharmaceutical composition of embodiment 195, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about50 mg and about 1000 mg.

Embodiment 204

The pharmaceutical composition of embodiment 195, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is between about200 mg and about 700 mg.

Embodiment 205

The pharmaceutical composition of embodiment 195, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 400 mg.

Embodiment 206

The pharmaceutical composition of embodiment 195, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 500 mg.

Embodiment 207

The pharmaceutical composition of embodiment 195, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 600 mg.

Embodiment 208

The pharmaceutical composition of embodiment 195, wherein the combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride is about 700 mg.

Embodiment 209

The pharmaceutical composition of embodiment 195, wherein the(R)-(+)-amisulpride is present in an amount between about 300 mg toabout 600 mg and the (S)-(−)-amisulpride is present in an amount betweenabout 40 mg to about 105 mg.

Embodiment 210

A composition according to any of embodiments 1-53 or embodiments178-209 used for the treatment of a psychiatric disorder.

Embodiment 211

The composition of embodiment 210 wherein the psychiatric disorder is adepressive disorder.

Embodiment 212

The composition of embodiment 211 wherein the psychiatric disorder ismajor depressive disorder (MDD).

Embodiment 213

The composition of embodiment 210 wherein the psychiatric disorder ismajor depressive disorder with mixed features (MDD-MF).

Embodiment 214

The composition of embodiment 210 wherein the psychiatric disorder istreatment resistant depression (TRD).

Embodiment 215

The composition of embodiment 210 wherein the psychiatric disorder isone or more of schizophrenia and negative symptoms of schizophrenia.

Embodiment 216

The composition of embodiment 210 wherein the psychiatric disorder isbipolar disorder.

Embodiment 217

The composition of embodiment 210 wherein the psychiatric disorder isbipolar depression.

Embodiment 218

The composition of embodiment 210 wherein the psychiatric disorder istwo or more of schizophrenia, negative symptoms of schizophrenia,treatment resistant depression, bipolar disorder and depression.

Embodiment 219

Use of a composition according to any of embodiments 1-53 or embodiments178-209 in the manufacture of a medicament for the treatment of apsychiatric disorder.

Embodiment 220

The medicament of embodiment 219 wherein the psychiatric disorder is adepressive disorder.

Embodiment 221

The medicament of embodiment 220 wherein the psychiatric disorder ismajor depressive disorder (MDD).

Embodiment 222

The medicament of embodiment 219 wherein the psychiatric disorder ismajor depressive disorder with mixed features (MDD-MF).

Embodiment 223

The medicament of embodiment 219 wherein the psychiatric disorder istreatment resistant depression (TRD).

Embodiment 224

The medicament of embodiment 219 wherein the psychiatric disorder is oneor more of schizophrenia and negative symptoms of schizophrenia.

Embodiment 225

The medicament of embodiment 219 wherein the psychiatric disorder isbipolar disorder.

Embodiment 226

The medicament of embodiment 219 wherein the psychiatric disorder isbipolar depression.

Embodiment 227

The medicament of embodiment 219 wherein the psychiatric disorder is twoor more of schizophrenia, negative symptoms of schizophrenia, treatmentresistant depression, bipolar disorder and depression.

The present disclosure also provides the following embodiments:

Embodiment 1A

A pharmaceutical composition comprising:

an amount between about 85 mg and about 600 mg of (R)-(+)-amisulpride,or a pharmaceutically acceptable salt thereof, by weight of free base;and

an amount between about 15 mg and about 100 mg (S)-(−)-amisulpride, or apharmaceutically acceptable salt thereof, by weight of free base;

in the enantiomeric ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpridebetween about 65:35 and about 88:12 by weight of free base.

Embodiment 2A

The pharmaceutical composition of embodiment 1A wherein the ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is between about 75:25 toabout 88:12 by weight of free base.

Embodiment 3A

The pharmaceutical composition of embodiment 1A or 2A wherein the ratioof (R)-(+)-amisulpride to (S)-(−)-amisulpride is between about 80:20 toabout 88:12 by weight of free base.

Embodiment 4A

The pharmaceutical composition of any one of embodiments 1A-3A whereinthe ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride is between about85:15 by weight of free base.

Embodiment 5A

The pharmaceutical composition of any one of embodiments 1A-4Acomprising:

an amount between about 170 mg and about 340 mg of (R)-(+)-amisulpride,or a pharmaceutically acceptable salt thereof, by weight of free base;and

an amount between about 30 mg and about 60 mg (S)-(−)-amisulpride, or apharmaceutically acceptable salt thereof, by weight of free base.

Embodiment 6A

The pharmaceutical composition of any one of embodiments 1A-5Acomprising:

an amount about 170 mg of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base; and

an amount about 30 mg of (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base.

Embodiment 7A

The pharmaceutical composition of any one of embodiments 1A-5Acomprising:

an amount about 340 mg of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base; and

an amount about 60 mg of (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base.

Embodiment 8A

The pharmaceutical composition of any one of embodiments 1A-4A, whereinthe combined amount of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, and (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, is about 100 mg, 200 mg, 300 mg, 400 mg, 500mg, 600 mg or 700 mg by weight of free base.

Embodiment 9A

The pharmaceutical composition of any one of embodiments 1A-4A, whereinthe combined amount of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, and (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, is between about 200 mg and about 600 mg byweight of free base.

Embodiment 10A

The pharmaceutical composition of any one of embodiments 1A-4A and 9A,wherein the combined amount of (R)-(+)-amisulpride, or apharmaceutically acceptable salt thereof, and (S)-(−)-amisulpride, or apharmaceutically acceptable salt thereof, is between about 200 mg andabout 400 mg by weight of free base.

Embodiment 11A

The pharmaceutical composition of any one of embodiments 1A-4A and8A-10A, wherein the combined amount of (R)-(+)-amisulpride, or apharmaceutically acceptable salt thereof, and (S)-(−)-amisulpride, or apharmaceutically acceptable salt thereof, is about 200 mg by weight offree base.

Embodiment 12A

The pharmaceutical composition of any one of embodiments 1A-4A and8A-10A, wherein the combined amount of (R)-(+)-amisulpride, or apharmaceutically acceptable salt thereof, and (S)-(−)-amisulpride, or apharmaceutically acceptable salt thereof, is about 400 mg by weight offree base.

Embodiment 13A

The pharmaceutical composition of any one of embodiments 1A-12A, whereinthe (R)-(+)-amisulpride is crystalline (R)-(+)-amisulpride of crystalForm A; and the (S)-(−)-amisulpride is crystalline (S)-(−)-amisulprideof crystal Form A′.

Embodiment 14A

The pharmaceutical composition of any one of embodiments 1A-13Acomprising a combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,effective to provide in the subject after administration an occupancy ofdopamine D2 receptors between about 20% and about 60%.

Embodiment 15A

The pharmaceutical composition of any one of embodiments 1A-14Acomprising a combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,effective to provide in the subject after administration an occupancy ofdopamine D2 receptors between about 30% and about 50%.

Embodiment 16A

The pharmaceutical composition of any one of embodiments 1A-15Acomprising a combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,effective to provide in the subject after administration a suppressionof the time in rapid eye movement (REM) sleep as characterized by adecrease in REM sleep by an amount greater than about 10 minutes.

Embodiment 17A

The pharmaceutical composition of any one of embodiments 1A-16Acomprising a combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,effective to provide in the subject after administration a suppressionof the time in rapid eye movement (REM) sleep as characterized by adecrease in REM sleep by an amount between about 15 minutes and about 45minutes.

Embodiment 18A

The pharmaceutical composition of any one of embodiments 1A-17Acomprising a combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,effective to provide in the subject after administration a suppressionof the time in rapid eye movement (REM) sleep as characterized by adecrease in REM sleep by an amount between about 15 minutes and about 30minutes.

Embodiment 19A

The pharmaceutical composition of any one of embodiments 1A-18Acomprising a combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,effective to provide in the subject after administration a suppressionof the time in rapid eye movement (REM) sleep as characterized by alatency to REM sleep by an amount greater than about 20 minutes.

Embodiment 20A

The pharmaceutical composition of any one of embodiments 1A-19Acomprising a combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,effective to provide in the subject after administration a suppressionof the time in rapid eye movement (REM) sleep as characterized by alatency to REM sleep by an amount greater than about 30 minutes.

Embodiment 21A

The pharmaceutical composition of any one of embodiments 1A-20Acomprising a combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,effective to provide in the subject after administration a suppressionof the time in rapid eye movement (REM) sleep as characterized by adecrease in total REM sleep time relative to total sleep time by anamount greater than about 5%.

Embodiment 22A

The pharmaceutical composition of any one of embodiments 1A-21Acomprising a combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,effective to provide in the subject after administration a suppressionof the time in rapid eye movement (REM) sleep as characterized by adecrease in total REM sleep time relative to total sleep time by anamount greater than about 6.5%.

Embodiment 23A

The pharmaceutical composition of any one of embodiments 1A-13Acomprising a combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof,effective to provide in the subject after administration:

an occupancy of dopamine D2 receptors between about 30% and about 50%;and

a suppression of the time in rapid eye movement (REM) sleep by an amountbetween about 15 minutes and about 45 minutes.

Embodiment 24A

A pharmaceutical composition comprising an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, wherein the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride, and wherein the amountof (R)-(+)-amisulpride and (S)-(−)-amisulpride in the composition iseffective to provide in a subject after administration:

an occupancy of dopamine D2 receptors between about 20% and about 60%;and

a suppression of time in rapid eye movement (REM) sleep as characterizedby one or more of:

a decrease in REM sleep by an amount greater than about 10 minutes,

a latency to REM sleep by an amount greater than about 20 minutes, or

a decrease in total REM sleep time relative to total sleep time by anamount greater than about 5%.

Embodiment 25A

The pharmaceutical composition of embodiment 24A, wherein the occupancyof dopamine D2 receptors is between about 30% and about 50%.

Embodiment 26A

The pharmaceutical composition of embodiment 24A or 25A, wherein thedecrease in REM sleep is between about 15 minutes and about 45 minutes.

Embodiment 27A

The pharmaceutical composition of any one of embodiments 24A-26A,wherein the latency to REM sleep is by an amount greater than about 30minutes.

Embodiment 28A

The pharmaceutical composition of any one of embodiments 24A-27A,wherein the decrease in total REM sleep time relative to total sleeptime is by an amount greater than about 6.5%.

Embodiment 29A

The pharmaceutical composition of any one of embodiments 24A-28A whereinthe ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride is between about85:15 by weight of free base.

Embodiment 30A

The pharmaceutical composition of any one of embodiments 24A-29A,wherein the combined amount of (R)-(+)-amisulpride, or apharmaceutically acceptable salt thereof, and (S)-(−)-amisulpride, or apharmaceutically acceptable salt thereof, is between about 100 mg andabout 700 mg by weight of free base.

Embodiment 31A

A pharmaceutical composition comprising an unequal mixture of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, wherein the amount of (R)-(+)-amisulpride isgreater than the amount of (S)-(−)-amisulpride, in amounts effective toprovide in a subject after administration:

inhibition of dopamine D2 activity and serotonin 5-HT7 activity in saidsubject such that the ratio of the serotonin 5-HT7 receptor inhibitoryconstant to the dopamine D2 receptor inhibitory constant is in the rangebetween about 2 to about 6.

Embodiment 32A

The pharmaceutical composition of embodiment 31A, wherein the ratio ofthe serotonin 5-HT7 receptor inhibitory constant to the dopamine D2receptor inhibitory constant is in the range between about 3 to about 5.

Embodiment 33A

The pharmaceutical composition of embodiment 31A or 32A, wherein theratio of the serotonin 5-HT7 receptor inhibitory constant to thedopamine D2 receptor inhibitory constant is about 4.

Embodiment 34A

The pharmaceutical composition of any one of embodiments 31A-33A,wherein the dopamine D2 receptor inhibitory constant is in the rangebetween about 11 nM to about 20 nM and the serotonin 5-HT7 receptorinhibitory constant is in the range between about 40 nM to about 85 nM.

Embodiment 35A

The pharmaceutical composition of any one of embodiments 31A-34A,wherein the dopamine D2 receptor inhibitory constant is about 17 nM andthe serotonin 5-HT7 receptor inhibitory constant is about 66 nM.

Embodiment 36A

The pharmaceutical composition of any one of embodiments 1A-35A, whereinthe composition is provided in a solid oral dosage form comprising oneor more pharmaceutically acceptable excipients.

Embodiment 37A

The pharmaceutical composition of embodiment 36A, wherein

the total combined amount of (R)-amisulpride and (S)-amisulpridecomprises between about 20% to about 40% of the total weight of thepharmaceutical composition; and

-   -   the one or more pharmaceutically acceptable excipients comprise:

a filler comprising between about 30% and about 55% of the total weightof the pharmaceutical composition; and

a disintegrant comprising between about 15% and about 30% of the totalweight of the pharmaceutical composition.

Embodiment 38A

A liquid pharmaceutical composition comprising:

one or more pharmaceutically acceptable excipients; and

an aqueous solution comprising an unequal mixture of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, and(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof, witha combined amount between about 5 mg/mL and about 200 mg/mL, wherein theratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride is in the rangebetween about 65:35 to about 88:12 by weight of free base.

Embodiment 39A

A method of treating a psychiatric disorder in a subject comprisingadministering a pharmaceutical composition of any one of embodiments1A-38A.

Embodiment 40A

The method of embodiment 39A wherein the psychiatric disorder is adepressive disorder.

Embodiment 41A

The method of embodiment 39A wherein the psychiatric disorder is majordepressive disorder (MDD).

Embodiment 42A

The method of embodiment 39A wherein the psychiatric disorder is majordepressive disorder with mixed features (MDD-MF).

Embodiment 43A

The method of embodiment 39A wherein the psychiatric disorder istreatment resistant depression (TRD).

Embodiment 44A

The method of embodiment 39A wherein the psychiatric disorder is one ormore of schizophrenia and negative symptoms of schizophrenia.

Embodiment 45A

The method of embodiment 39A wherein the psychiatric disorder isschizoaffective disorder.

Embodiment 46A

The method of embodiment 39A wherein the psychiatric disorder is bipolardisorder.

Embodiment 47A

The method of embodiment 39A wherein the psychiatric disorder is bipolardepression.

Embodiment 48A

The method of embodiment 39A wherein method of treatment treats two ormore of schizophrenia, negative symptoms of schizophrenia, treatmentresistant depression, bipolar disorder and depression.

Embodiment 49A

The method of any one of embodiments 39A-48A wherein the composition isadministered once daily.

Embodiment 50A

A method of treating bipolar depression comprising administering oncedaily to a subject in need thereof an effective amount of a compositioncomprising:

an amount about 170 mg of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base; and

an amount about 30 mg of (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base.

Embodiment 51A

A method of treating bipolar depression comprising administering oncedaily to a subject in need thereof an effective amount of a compositioncomprising:

-   -   an amount about 340 mg of (R)-(+)-amisulpride, or a        pharmaceutically acceptable salt thereof, by weight of free        base; and    -   an amount about 60 mg of (S)-(−)-amisulpride, or a        pharmaceutically acceptable salt thereof, by weight of free        base.

Embodiment 52A

A method of inhibiting dopamine D2 activity and serotonin 5-HT7 activityin a subject, comprising administering to a subject an effective amountof an unequal mixture of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, and (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof.

As used herein the term “polymorph purity” refers to the weight % thatis the specified polymorph form. For example, when a crystalline(R)-amisulpride Form A is characterized as having greater than 95%polymorph purity, that means that greater than 95% by weight of thesubstance is crystalline (R)-amisulpride of Form A and less than 5% byweight of any other polymorph or amorphous form of (R)-amisulpride.

As used herein the terms “chiral purity” and “enantiomeric purity” areused interchangeably and refers to the weight % that is the specifiedenantiomer. For example, when a (R)-amisulpride containing substance(such as a compound or crystal) is characterized as having greater than90% chiral purity, that means that greater than 95% by weight of theamisulpride in the substance is the (R)-amisulpride and less than 5% byweight is in any other enantiomeric form of amisulpride.

As used herein the term “chemical purity” refers to the weight % that isthe specified chemical entity, including specified polymorph form. Forexample, when a crystalline amisulpride Form A is characterized ashaving greater than 95% chemical purity, that means that greater than95% by weight of the substance is crystalline amisulpride Form A andless than 5% by weight of other compound including other polymorphs.

For example, when a crystalline (R)-amisulpride Form A is characterizedas having greater than 99% chemical purity and greater than 97% chiralpurity, that means greater than 97% by weight of the substance is ofenantiomeric form (R)-amisulpride Form A and less than 3% by weight ofany other amisulpride enantiomer, and that greater than 99% by weight ofthe substance is amisulpride and less than 1% by weight of othercompounds. For example, when a crystalline (R)-amisulpride Form A ischaracterized as having greater than 99% chemical purity, greater than97% chiral purity and greater than 95% polymorph purity, that means thatgreater than 95% by weight of the substance is crystalline(R)-amisulpride of Form A and less than 5% by weight of any otherpolymorph or amorphous form of (R)-amisulpride, greater than 97% byweight of the substance is of enantiomeric form (R)-amisulpride and lessthan 3% by weight of any other amisulpride enantiomer, and that greaterthan 99% by weight of the substance is amisulpride and less than 1% byweight of other compounds.

Chemical purity may be characterized using a number of conventionalanalytical techniques, including but not limited to high performanceliquid chromatography (HPLC) and gas chromatography (GC). Chiral purity(also known as enantiomeric purity) may be characterized using a numberof conventional analytical techniques, including but not limited tochiral high performance liquid chromatography (HPLC). Water content maybe characterized using a number of conventional analytical techniques,including but not limited to coulometric titration.

For example, in various embodiments, crystalline (R)-amisulpride of FormA, crystalline (S)-amisulpride of Form A′, or both, are provided asactive ingredients that have a greater than about 90% polymorph purity,greater than about 95% polymorph purity, greater than about 97%polymorph purity, greater than about 99% polymorph purity, greater thanabout 99.5% polymorph purity, greater than about 99.7% polymorph purity,or greater than about 99.9% polymorph purity.

For example, in various embodiments, crystalline (R)-amisulpride of FormA, crystalline (S)-amisulpride of Form A′, or both, are provided asactive ingredients that have a greater than about 95% chemical purity,greater than about 97% chemical purity, greater than about 99% chemicalpurity, greater than about 99.5% chemical purity, greater than about99.7% chemical purity, or greater than about 99.9% chemical purity. Invarious embodiments, crystalline (R)-amisulpride of Form A, crystalline(S)-amisulpride of Form A′, or both, are provided that has less thanabout 8000 ppm residual solvents, less than about 6000 ppm residualsolvents, less than about 4000 ppm residual solvents, less than about2000 ppm residual solvents, less than about 1000 ppm residual solvents,less than about 800 ppm residual solvents, or less than about 500 ppmresidual solvents.

Aspects, embodiments, and features of the inventions may be furtherunderstood from the following examples, which should not be construed aslimiting the scope of the inventions. Example 1 presents in vitro data,Examples 2 and 3 animal study data, and Examples 4-6 present humanclinical data.

Example 1: In Vitro Assays of Dopamine D2 and Serotonin 5-HT7 Affinities

Amisulpride enantiomers and racemic amisulpride were tested for affinityto Dopamine D₂s receptors recombinantly expressed in human ChineseHamster Ovary (CHO) cells by radioligand binding techniques (EurofinsPanlabs, Inc.). The receptors' B_(max) value was 1.6 pmole/mg protein.The radioligand was [3H]Spiperone at 0.16 nM concentration with 0.090 nMdissociation constant (Kd, historical value under identical laboratoryconditions). The incubation buffer was 50 mM Tris-HCl, pH 7.4, 1.4 mMascorbic acid, 0.001% BSA, and 150 mM NaCl. The amisulpride compoundunder study (e.g., enantiomeric amisulprides and racemic amisulpride)was dissolved in dimethyl sulfoxide (DMSO) and added to the assay wellsfor a 1% final concentration. Percent inhibition values of specificbinding by amisulpride enantiomers and racemic amisulpride weregenerated with 12 serial dilutions from 10 micromolar down to 3 nM finalconcentrations. Each concentration was tested in duplicate. Amisulprideenantiomer affinities and racemic amisulpride affinities for dopamine D2receptors are based on the average of 3 independent experiments.Affinities were calculated with the Cheng-Prusoff equation and theobserved IC50 of the tested compound, the concentration of radioligandemployed in the assay, and the historical value for the Kd of the ligand(obtained experimentally).

Amisulpride enantiomers and racemic amisulpride were tested for affinityto Serotonin 5-HT₇ receptors recombinantly expressed in human CHO-K1cells by radioligand binding techniques (Eurofins Panlabs, Inc.). Thereceptors' B_(max) value was 0.95 pmole/mg protein. The radioligand is[3H]Lysergic acid diethylamide (LSD) at 5.5 nM concentration with 7.40nM dissociation constant (Kd, historical value under identicallaboratory conditions). The incubation buffer was 50 mM Tris-HCl, pH7.4, 10 mM MgCl₂, 0.5 mM EDTA. The amisulpride compound under study(e.g., enantiomeric amisulprides and racemic amisulpride) was dissolvedin DMSO and added to the assay wells for a 1% final concentration.Percent inhibition values of specific binding by amisulpride enantiomersand racemic amisulpride were generated with 12 serial dilutions from 10micromolar down to 3 nM final concentrations. Each concentration wastested in duplicate. Amisulpride enantiomer affinities and racemicamisulpride affinities for serotonin 5-HT7 receptors are based on theaverage of 3 independent experiments. Affinities were calculated withthe Cheng-Prusoff equation and the observed IC50 of the tested compound,the concentration of radioligand employed in the assay, and thehistorical value for the Kd of the ligand (obtained experimentally).

Percent inhibition of specific binding was determined as a function oftest drug concentration (i.e., (R)-amisulpride (S)-amisulpride, andracemic amisulpride). It was discovered that there are distinctpharmacological activities with the potential for combined clinicalbenefit which reside in opposite enantiomers.

Referring to FIG. 1A, depicted is the data on the % inhibition ofdopamine D2 binding of Example 1 for (R)-amisulpride (downwardtriangle), (S)-amisulpride (upward triangle), and racemic amisulpride(circle). The vertical bars represent ±1 standard deviation from the 3independent determinations. FIG. 1A illustrates that the (S)-enantiomeris the more potent enantiomer for dopamine D₂ receptors.

Referring to FIG. 1B, depicted is the data on the % inhibition ofserotonin 5-HT7 binding of Example 1 for (R)-amisulpride (downwardtriangle), (S)-amisulpride (upward triangle), and racemic amisulpride(circle). The vertical bars represent ±1 standard deviation from the 3independent determinations. FIG. 1B illustrates that the (R)-enantiomeris more potent in inhibiting binding to serotonin 5-HT₇ receptors.

Table 4 summarizes inhibitor constant (Ki) values in nM determined invitro by radioligand binding and compares racemic amisulpride to amixture of (R)-(+)-amisulpride and (S)-(−)-amisulpride of about 85:15 byweight. Human dopamine D₂ receptors or human serotonin 5-HT₇ receptorswere expressed in CHO cells or CHO-K1 cells, respectively. Standarderror of the mean is presented based on multiple, independentdeterminations.

TABLE 4 (R)-amisulpride : Racemic (S)-amisulpride (50:50) (85:15)Dopamine D₂ 7.1 ± 0.26  17 ± 0.62 Serotonin 5-HT₇ 89 ± 2  66 ± 16 5-HT₇/ D₂ 13 4

Example 1 shows that the (R)-enantiomer is highly stereoselective forserotonin 5-HT7 receptors such that the 5-HT7 antagonism of amisulprideresides almost exclusively in the (R)-enantiomer and that the(S)-enantiomer is highly stereoselective for dopamine D2 receptors suchthat the D2 antagonism of racemic amisulpride resides predominantly inthe (S)-enantiomer. Referring to again to FIG. 1A, the D2 antagonism of(S)-amisulpride was determined to be about 20 fold that of the(R)-amisulpride, and referring to again to FIG. 1B, the 5-HT7 antagonismof (R)-amisulpride was determined to be about 300 fold that of the(S)-amisulpride.

Referring to FIG. 1C, depicted is the data on relative receptor affinity(5-HT7: D2) for various mixtures of (R)-amisulpride and (S)-amisulpride,determined in accordance with the procedures of Example 1, where thex-axis indicates the percentage of the tested drug that was(R)-amisulpride, the remainder percentage being (S)-amisulpride. Table 5lists for various weight ratios (R)-amisulpride to (S)-amisulpride(first column), from the (S)-enantiomer alone (0:100 ratio) to(R)-enantiomer alone (100:0 ratio), the Ki values (average±1 standarddeviation) in nM for n=3 independent determinations, for dopamine D2(second column) and serotonin 5-HT7 (third column), and the ratio of5-HT7 to D2 Ki values (fourth column and plotted in FIG. 1C).

TABLE 5 Ki Values for Enantiomeric Amisulpride and Mixtures ofAmisulpride Enantiomers in vitro Ki values Ratio Ratio D2 Ki 5-HT7 5-HT7R:S (nM) (nM) D2  0:100 4.43 ± 0.70 1,860 ± 260  420 50:50 7.10 ± 0.2689 ± 2 13 60:40 7.51 ± 0.57 79 ± 4 11 65:35 6.50 ± 0.64 79 ± 9 12 70:308.54 ± 1.61 72 ± 4 8 75:25 8.16 ± 0.17 59 ± 6 7 80:20   12 ± 0.73  59 ±10 5 85:15   16 ± 0.62  66 ± 16 4 90:10 18.9 ± 0.95 48 ± 8 3 100:0  140± 31  47 ± 4 0.3

Examples 2, 3A, and 3B: Animal Studies

A series of animal studies were performed on rats with various doses of(R)-amisulpride.

Example 2: Forced Swim Test

The Forced Swim test (FST) is an indicator of the antidepressant-likeactivity of a test compound. The rat will swim before “giving up” andbecoming immobile. A compound with antidepressant-like activity willdecrease the time the rat is immobile.

The animals (n=90) were divided into five groups. Animals in four groupswere treated with one of the three doses of (R)-amisulpride orimipramine (control), whereas those in the other group received onlyvehicle (M phosphoric acid+0.1 M NaOH (pH6-7)). In the training session,each animal was gently placed into the plastic cylinder containing 5.8 Lof water set at 25±1° C. Fifteen minutes after the beginning of thetraining session, the animal was removed from the water. The dosingsolutions were administered 15 minutes after finishing of the training.

Prior to the swim test, animals were intraperitoneally administeredvehicle (1 ml/kg), imipramine (10 mg/kg) or (R)-amisulpride (0.15, 0.5and 1.5 mg/kg) at 24 hours, 5 hours and 1 hour prior to the swim test.The swim test was performed for 5 minutes in the same manner as thetraining session. In the swim test, the behavior of each animal washorizontally recorded using a video camera. After the swim test, animalswere immediately sacrificed by inhalation of carbon dioxide.

The swim movies were handled in a blind manner to ensure that the personwho measured the immobility time had no information on the treatment. Ananimal was judged to be immobile whenever it remained floating in thewater without moving its body or forepaws except for the slight movementto maintain its posture. The total time for which the animal remainedimmobile was defined as the immobility time. An observer blinded to thedoses measured the immobility times. The immobility time of each animalwas measured to one decimal place and rounded to a whole number.Immobility time was expressed in units of seconds. In each series themeans of immobility time were calculated and rounded to a whole numberusing. The mean and standard error (SE) for each group were calculatedusing the data obtained from three experimental series and rounded to awhole number. All results are represented as the mean±SE.

The data of imipramine were analyzed using t-test with a two-sidedsignificance level of 5% (p<0.05). In the case imipramine significantlydecrease the immobility time compared to control, the data of(R)-amisulpride were then analyzed parametrically using Dunnett'smultiple comparison test with a two-sided significance level of 5%(p<0.05). The data is presented in FIG. 2.

Referring to FIG. 2, data is presented for vehicle, imipramine(comparator), and 0.15, 0.5 and 1.5 mg/kg of (R)-amisulpride. Theimmobility time values are mean±standard error of the mean (SEM). Thesymbol ## indicates a p-value of p<0.01 vs. vehicle (determined using atwo-sided t-test); * indicates a p-value of p<0.05 and ** indicates ap-value of p<0.01 vs. vehicle (determined using a parametric two-sidedDunnett's multiple comparison test).

The immobility time of animals in the vehicle-treated group was 168±12sec. Imipramine of 10 mg/kg shortened the immobility time by more than20% in all series and the immobility time average was 105±15 sec, whichwas significantly shorter than the average of vehicle-treated group.Animals treated with (R)-amisulpride at doses of 0.15, 0.5, and 1.5mg/kg had immobility times of 142±11, 124±12 and 111±16 sec,respectively. (R)-amisulpride significantly decreased the immobilitytime at 0.5 and 1.5 mg/kg comparable to imipramine) indicative ofantidepressant-like activity for (R)-amisulpride.

Example 3A: Sleep Study of (R)-Amisulpride

In rodents, 5-HT7 receptor blockade has been shown to be effective inmodels of depression and to increase the latency to REM sleep anddecrease REM duration.

In this study, the effect of (R)-amisulpride on sleep architecture infreely moving rats in the light phase was evaluated. Rapid eye movement(REM) sleep time, non-rapid eye movement (NREM) sleep time, WAKE timewere measured using electroencephalogram (EEG) and electromyogram (EMG)recordings. (R)-amisulpride (10, 30, 100 mg/kg, p.o.) was administered10 min before the beginning of recording, during the light phase. EEGand EMG recordings were made for 6 hr starting at the beginning of thelight phase. Vehicle (0.05 N HCl/0.5% Methyl Cellulose 400 solution) ordosing suspensions were orally administered 10 min before the beginningof light phase. The volume of administration was 5 mL/kg. The order ofdrug treatment varied pseudo-randomly and at least 1 week was allowedbetween the experiments for individual animals.

A radio transmitter (TL11M2-F40-EET; Data Science International, NewBrighton, Minn., USA) was implanted subcutaneously in the back ofanesthetized animals, and a pair of electrode wires was stereotaxicallyimplanted into the skull in the following locations: one in thefrontoparietal (2 mm anterior to the bregma and 2 mm left to themidline), and the other in parietal (5 mm posterior to the bregma and 2mm right to the midline) areas. The EEG electrodes were fixed usingdental cement. Electromyograms (EMG) were recorded from the dorsal neckmuscle. The animals, then, were allowed at least 1 week recovery inindividual plastic cages before EEG/EMG recording. EEG/EMG were recordedin the home cages in a soundproof box using Dataquest A.R.T. software(Data Science International, New Brighton, Minn., USA) at a samplingrate of 500 Hz.

Sleep stage analysis was conducted off-line using Sleepsign software(KISSEI COMTEC CO., LTD, Nagano, Japan). Electrographic activity of10-sec epochs were analyzed and each epoch was automatically assigned asWAKE, REM, and NREM based on the waveforms of EEG and EMG according tothe following definitions: WAKE was defined as a condition in which EMGexceeded the individual threshold, NREM was defined as a condition inwhich the power of delta waves (0.5-4 Hz) exceeded the individualthreshold with no EMG activity, and REM was defined as a condition inwhich the power of theta waves (4-8 Hz) exceeded 40% of the total powerof frequencies between 0.5 and 80 Hz in the presence of no EMG activity.The duration of each REM, WAKE, and NREM periods were calculated bysumming time spent in each condition during sleep every 2 hours.

Referring to FIG. 3A (n=6) and 3B (n=7), data is presented for vehicleand 10 mg/kg, 30 mg/kg and 100 mg/kg of (R)-amisulpride. The y-axisrepresents the time in minutes that REM sleep was suppressed and thesevalues are mean±standard error of the mean (SEM). The symbol * indicatesa p-value of p<0.05, ** indicates a p-value of p<0.01; and *** indicatesa p-value of p<0.001; (determined using a two-way ANOVA followed bypost-hoc parametric Dunnett multiple comparison test).

All data are expressed as means±S.E.M. REM sleep, NREM sleep time, andWAKE time each of sequential 2-hr periods were compared statisticallyusing a repeated measures two-way ANOVA, followed by post-hoc Dunnetttests. All statistical analyses were performed using GraphPad Prism 6software (GraphPad Software, Inc., CA, USA, ver. 6.03J).

It was determined that (R)-amisulpride (10, 30, 100 mg/kg, p.o.)treatment reduced REM sleep duration in dose-dependent manner in freelymoving rat, with significant reductions in REM sleep duration following100 mg/kg in the 0-2 hr and 2-4 hr periods (time after administration).There was no observed effect of (R)-amisulpride on NREM sleep time andWAKE time.

Example 3B: Sleep Study of 85:15 (R:S-Amisulpride) and RacemicAmisulpride

In rodents, 5-HT7 receptor blockade has been shown to be effective inmodels of depression and to increase the latency to REM sleep anddecrease REM duration.

In this study, the effect of 85:15 (R:S-amisulpride) and racemicamisulpride on sleep architecture in freely moving rats in the lightphase was evaluated. Groups in this study were as follows. Test compoundwas administered to rats in a cross-over design.

Fixed Total dose Number Group ratio (R/S dose) of No. amisulpride(mg/kg) animals 1 Vehicle (*) 7 2 R/S = 50/50  30 (15/15) 3 R/S = 85/15  30 (25.5/4.5) 4 R/S = 50/50 100 (50/50) 5 R/S = 85/15 100 (85/15) (*)0.05N HCl/0.5% MC treatment

Vehicle or fixed ratio amisulpride dosing solutions were orallyadministered 10 min before the beginning of light phase (light phase:10:00 AM to 10:00 PM). The individual dosing volume was 4 mL/kg. Theindividual dosing volume was calculated based on the animals' bodyweight measured on each experimental day. At least 1-week wash-outperiod after each treatment was provided.

Animal Treatments (R/S ratio; Dose mg/kg) No. 1^(st) 2^(nd) 3^(rd)4^(th) 5^(th) Rat 1 Vehicle 50/50; 100 85/15; 100 50/50; 30 85/15; 30Rat 2 50/50; 100 Vehicle 85/15; 100 50/50; 30 85/15; 30 Rat 3 Vehicle50/50; 100 85/15; 100 50/50; 30 85/15; 30 Rat 4 50/50; 100 Vehicle85/15; 100 50/50; 30 85/15; 30 Rat 5 Vehicle 50/50; 100 85/15; 10050/50; 30 85/15; 30 Rat 6 Vehicle 50/50; 100 85/15; 100 50/50; 30 85/15;30 Rat 7 50/50; 100 Vehicle 85/15; 100 50/50; 30 85/15; 30

The R-amisulpride and S-amisulpride were separately weighed. The vehicle(0.05 N HCl/0.5% MC solution) was then added to prepare each solutionwith a concentration of 25 mg/mL (100 mg/kg dosing solution) or 7.5mg/mL (30 mg/kg dosing solution). Fixed-ratio amisulpride (R/S=85/15 or50/50) solution (i.e. a dosing formulation) was prepared by mixingR-amisulpride and S-amisulpride solution.

A radio transmitter was implanted intraperitoneally in each anesthetizedanimal (sodium pentobarbital, 32.4 mg/kg, i.p. and medetomidinehydrochloride, 0.5 mg/kg, i.p.). A pair of electrode wires wasstereotaxically implanted into the skull in the following locations: onein the frontoparietal (2 mm anterior to the bregma and 2 mm left to themidline), and the other in parietal (5 mm posterior to the bregma and 2mm right to the midline) areas. The electroencephalogram (EEG)electrodes were fixed using dental cement. Electromyograms (EMG) wererecorded from the dorsal neck muscle. The animals were allowed at least2 weeks recovery in individual plastic cages before EEG/EMG recording.EEG/EMG was recorded in the home cages in a soundproof box usingDataquest A.R.T. software (Data Science International, New Brighton,Minn., USA) at a sampling rate of 500 Hz.

Sleep stage analysis was conducted off-line using Sleepsign software(KISSEI COMTEC CO., LTD, Japan). Electrographic activity of 10-secepochs were analyzed and each epoch was automatically assigned as WAKE,REM, and NREM based on the waveforms of EEG and EMG according to thefollowing definitions: WAKE was defined as a condition in which EMGexceeded the individual threshold, NREM was defined as a condition inwhich the power of delta waves (0.5-4 Hz) exceeded the individualthreshold with no EMG activity, and REM was defined as a condition inwhich the power of theta waves (4-8 Hz) exceeded 40% of the total powerof frequencies between 0.5 and 80 Hz in the presence of no EMG activity.Based on the previous study which demonstrated that R-amisulpride wasactive 0 to 4 hours after administration (1), durations of REM sleep,NREM sleep, and WAKE were calculated using the data from the first 4hours after treatment.

All data were expressed as a mean±SEM. Difference between 85/15 and50/50 amisulpride at each dose in each sleep architecture (i.e. REMsleep duration, NREM sleep duration, and WAKE duration) during the first4 hours after administration were assessed by a repeated measuresone-way ANOVA, followed by post-hoc Bonferroni multiple comparison test.All statistical analyses were performed using GraphPad Prism 6 software(GraphPad Software, Inc., CA, USA, ver. 6.03J). P values less than 0.05were considered to be statistically significant.

FIG. 3C presents data comparing vehicle to 30 mg/kg and 100 mg/kg of85:15 ratio (R:S-amisulpride) and racemic amisulpride in REM sleep time(min). FIG. 3D presents data comparing vehicle to 30 mg/kg and 100 mg/kgof 85:15 ratio (R:S-amisulpride) and racemic amisulpride in NREM sleeptime (min). FIG. 3E presents data comparing vehicle to 30 mg/kg and 100mg/kg of 85:15 ratio (R:S-amisulpride) and racemic amisulpride in WAKEtime (min).

Results show that at total 30 mg/kg dose of amisulpride, the fixed ratio(R/S=85/15) demonstrated greater REM sleep time reduction (p=0.0495) andNREM sleep time increase (p=0.0083), compared to racemate (R/S=50/50).These differences in REM and NREM sleep times were not observed at total100 mg/kg dose of amisulpride. There was no difference between 85/15 and50/50 in WAKE time at any doses tested in this study. The intensity ofREM sleep suppression appeared to be dose-dependent on the amount ofR-amisulpride in the total dose. Indeed, each treatment, 30 mg/kg(50/50), 30 mg/kg (85/15), 100 mg/kg (50/50), and 100 mg/kg (85/15)contained 15, 25.5, 50, and 85 mg/kg of R-amisulpride, respectively.Greater REM sleep reduction was observed in the treatment groupadministered higher doses of R-amisulpride. The effect of R-amisulprideon REM sleep suppression was saturated at higher doses (i.e. ≥50 mg/kgof R-amisulpride). Similar effects were also observed in the NREM sleeptime.

In conclusion, the fixed ratio (R/S=85/15) amisulpride exhibits greaterREM sleep time reduction and NREM sleep time increase than those ofracemate (R/S=50/50) in freely moving rats.

Examples 4-6 Human Studies

A series of human clinical studies were performed with various doses of(R)-amisulpride, (S)-amisulpride, and an 85:15 ratio by weightpercentage (w/w %) mixture of (R)-amisulpride to (S)-amisulpride.

Example 4: Dopamine D₂ Receptor Occupancy PET Study

In these human clinical studies, each of the enantiomers is administeredto healthy human subjects in single doses to determine the maximumtolerated doses.

The minimum dose of (S)-amisulpride able to occupy Dopamine D2 receptorsin the brain at a clinically significant threshold for effect wasdetermined by administering single doses of (S)-amisulpride to healthyhuman volunteers participating in a Positron Emission Tomography (PET)clinical study. The set-point for minimum effective dose of(S)-amisulpride was the lowest dose level able to bind approximately onequarter to one third of brain Dopamine D₂ receptors in volunteers.

Dopamine D₂ occupancy of (S)-amisulpride following single oraladministration was performed in normal healthy volunteers using PositronEmission Tomography (PET) together with a highly selective D2 PETradiotracer. Subjects were enrolled into the study with the aim ofhaving a narrow (<2-fold) prediction interval for RO₅₀ (the doserequired for 50% D2 receptor occupancy). On day −1 (prior to doseadministration), baseline PET scans (2 hours) were performed for eachsubject and served as a control. On day 1, (S)-amisulpride was orallyadministered as a 10 ml oral solution prepared at the clinical sitepharmacy. The oral solution is a citrate buffer solution at pH 4.5containing citric acid monohydrate, trisodium citrate dihydrate andwater. The concentration can be determined from the amount of(S)-amisulpride and total volume. Dosages of 25 mg, 45 mg, 100 mg and200 mg were used. The selective D2 PET tracer (11C PHNO) was thenadministered intravenously prior to PET scans post-dose. At apredetermined time after PET tracer administration, post-dose PET scans(90 minute) were initiated and conducted at approximately 3, 8, and 27hours post-dose. Plasma samples were collected throughout the course ofthe PET scan session and were analyzed for (S)-amisulpride levels. Theplasma concentrations peaked in a 3 hour time frame and declinedseveral-fold to near baseline levels over the 27 hour time interval. Theelimination of (S)-amisulpride was consistent with the biphasicelimination half-life reported for amisulpride, which is characterizedby an initial elimination phase of 2 to 5 hours and a terminal plasmahalf-life of approximately 12 hours. (A. J. Coukell et al, CNS Drugs6(3), 237-256 (1996))

A Simplified Reference Tissue Model (SRTM) analysis with the caudate andputamen serving as the regions of interest (ROI) and cerebellum as thereference region was employed for estimating D₂ occupancy. To moreaccurately determine the relationship between D₂ occupancy and doses ofS-amisulpride, the observed D₂ occupancy for each dose/subject wasplotted against the derived plasma concentration to determine the doselevels associated with occupancies between 30% and 50% of brain DopamineD₂ receptors.

FIG. 4 presents analytical data from the human clinical studies (n=6) onthe effects of (S)-amisulpride binding to dopamine D2 receptors. The PETscans were conducted 27 hours post-dose, and the amount of(S)-amisulpride resulting in 50% occupancy (RO₅₀) was determined to be92 mg with a ±95% confidence interval of 72 mg to 124 mg.

It was unexpectedly discovered that given the declining plasmaconcentrations, stable D2 brain occupancies were nevertheless observedout to 27 hours. In comparison, another rapidly eliminated D2antagonist, quetiapine, has an elimination half-life of about 7 hoursand a D2 occupancy trough associated with the plasma concentrationtrough. (C. L. Delaney and C. B. Nemeroff, Clin. Pharmokinetics, 40 (7),509-522 (2001); D. C. Mamo et al., J. Clin. Psychiatry, 69:1, 81-86(2008)). Thus, it was surprisingly discovered that after 27 hours (overtwo full half-lives) the brain D2 occupancy in the study (Example 6 ofthe human studies) for subjects administered an 85:15 mixture((R)-amisulpride:(S)-amisulpride) was still as high as it was at 8 hourspost dose.

Example 5: REM Suppression Study

The minimum dose of (R)-amisulpride able to significantly suppress RapidEye Movement (REM) sleep in healthy volunteers to a clinicallysignificant effect was determined by administering (R)-amisulpride, as a20 ml oral solution prepared at the clinical site pharmacy, tovolunteers participating in a polysomnography (PSG) clinical study. Theoral solution is a citrate buffer solution at pH 4.5 containing citricacid monohydrate, trisodium citrate dihydrate and water. Theconcentration can be determined from the amount of (S)-amisulpride andtotal volume. REM suppression was the biomarker used to determineclinically-significant levels of 5-HT7 antagonism and itspharmacodynamics. REM suppression was assessed by total time in minutesspent in REM sleep and by the latency in minutes to REM sleep. It wasdetermined that an example minimum effective dose of (R)-amisulpride wasthe dose able to inhibit REM sleep by more than about 10 minutes. REMsuppression in human volunteers is an established translationalbiomarker useful to identify doses for antidepressant effects inpatients.

The dose of (R)-amisulpride able to suppress Rapid Eye Movement (REM)sleep in humans was identified in healthy subjects in a single-blind,placebo-controlled, randomized, 2-stage, 2-way crossover in-clinicpolysomnography (PSG) study of a single oral dose of (R)-amisulpride.Subjects receive a single dose of either (R)-amisulpride or placebo oneach of 2 sequential nights, subjects received drug on one night or theother of the two sequential nights. Two dose-levels of (R)-amisulpride(either 340 mg or 600 mg) were administered in the 2 different stages ofthe clinical study. The primary endpoint was REM sleep suppression asdetermined at post dose time points in the measures of latency to REMsleep, REM sleep time in minutes, and percent decrease in REM sleep timerelative to total sleep time.

FIG. 5 presents analytical data from the human clinical studies (n=33)on the effects of (R)-amisulpride in suppressing REM sleep. The REMsuppression time value is the Least Square Mean differences fromplacebo, and the error bars represent the 90% confidence interval (CI).Tables 6A-6C present data from this study.

The results presented in Tables 6A-6C were determined from an analysisof the date based on a linear mixed model with terms for treatment,period, and treatment sequence as fixed effects, respective baseline PSGvalue as a continuous covariate, and treatment-by-baseline PSGinteraction, and subject nested within sequence as a random effect, theKenward and Roger correction for the degrees of freedom and anunstructured covariance structure to model the intrasubject correlation.The abbreviations used in Tables 6A-6C are as follows:PSG=polysomnography; CI=confidence interval; LS=least-squares; REM=rapideye movement; SE=standard error.

TABLE 6A REM Suppression and % Decrease in REM Sleep Time(R)-amisulpride v Placebo Primary PSG LS Mean Endpoint LS MeanDifference (unit) Treatment n (SE) 90% CI (SE) 90% CI REM Time Placebo13 107.98 (5.65) (98.23, 117.72) −31.39 (7.99) (−45.17, −17.61)(Minutes) (R)-amisulpride 13 76.59 (5.65) (66.85, 86.33) 600 mg REM TimePlacebo 20 110.05 (4.69) (102.08, 118.02) −18.45 (4.91) (−26.99, −9.91)(Minutes) (R)-amisulpride 20 91.60 (4.69) (83.63, 99.57) 340 mg

TABLE 6B % Decrease in REM Sleep Time (R)-amisulpride v Placebo PrimaryPSG LS Mean Endpoint LS Mean Difference (unit) Treatment n (SE) 90% CI(SE) 90% CI REM Percent Placebo 13 24.30 (1.14) (22.33, 26.27) −6.24(1.45) (−8.87, −3.61) (%) (R)-amisulpride 13 18.06 (1.14) (16.09, 20.03)600 mg REM Percent Placebo 20 25.69 (0.92) (24.13, 27.25) −4.15 (1.09)(−6.04, −2.25) (%) (R)-amisulpride 20 21.55 (0.92) (19.98, 23.11) 340 mg

TABLE 6C Latency to REM Sleep (R)-amisulpride v Placebo Primary PSG LSMean Endpoint LS Mean Difference (unit) Treatment n (SE) 90% CI (SE) 90%CI Latency to Placebo 13 89.06 (7.71) (75.72, 102.40) 20.30 (9.39)(3.28, 37.31) REM Sleep (Minutes) (R)-amisulpride 13 109.35 (7.71)(96.01, 122.69) 600 mg Latency to Placebo 20 77.03 (9.42) (61.01, 93.04)28.23 (9.82) (11.15, 45.30) REM Sleep (Minutes) (R)-amisulpride 20105.25 (9.42) (89.23, 121.27) 340 mg

A single oral dose of 340 mg (R)-amisulpride was observed to result in adecrease in the time spent in REM sleep of 10-27 minutes, reducing theportion of the night spent in REM by 2-6 percentage points, andincreasing the latency to first REM by 11 to 45 minutes (ranges are for90% confidence intervals).

A single oral dose of 600 mg (R)-amisulpride was observed to result in adecrease in the time spent in REM sleep of 18-45 minutes, reducing theportion of the night spent in REM by 4-9 percentage points, andincreasing the latency to first REM by 3 to 37 minutes (ranges are for90% confidence intervals). Further, R-amisulpride was well tolerated inthis study. Of the 13 subjects dosed with 600 mg R-amisulpride, 3subjects reported adverse events. Vital signs and ECGs were normal.

The human clinical trials of Examples 4 and 5 identified distinctpharmacological effects between the R- and S-enantiomers of amisulpride.The dose-occupancy relationship of S-amisulpride identified minimaleffective doses of 25 mg to 100 mg for levels of D2 occupancies between20% to 50%. Additionally, a single dose of R-amisulpride (600 mg) wassufficient to produce clinically meaningful and statisticallysignificant suppression of REM sleep, indicating serotonergic (5-HT7)antagonism for R-amisulpride in humans.

Example 6: Dopamine D₂ Receptor Occupancy Study 85:15, R:S Mixture

In these human clinical studies, single oral doses of a fixed ratiocomposition of (R)-amisulpride to (S)-amisulpride of 85:15 by weightwere administered to healthy volunteers at total composition amounts of:200 mg (170 mg R-amisulpride:30 mg S-amisulpride); 300 mg (255 mgR-amisulpride:45 mg S-amisulpride); 400 mg (340 mg R-amisulpride:60 mgS-amisulpride); 600 mg (510 mg R-amisulpride:90 mg S-amisulpride); and700 mg (595 mg R-amisulpride:105 mg S-amisulpride). Doses wereadministered as a 20 mL oral solution in citrate buffer.

Dopamine D2 occupancy was measured by using Positron Emission Tomography(PET) together with a highly selective D2 and PET radiotracer 11C-PHNO.PET scans were performed prior to and post dosing. Dopamine D2 receptoroccupancy was calculated for each postdose PET scan via regionalestimate of the binding potential relative to the nondisplaceablecomponent (BPND). These estimates were derived using the simplifiedreference tissue model (SRTM) with the cerebellum serving as thereference region. Brain regions of interest that were considered includethe D2-rich regions such as caudate and putamen. Identification of brainregions was performed using co-registration of PET images with eachsubject's high-resolution T1-weighted MRI (structural brain) scan.

The primary endpoint of this study was to determine the relationshipbetween the dose (total mg) of the fixed ratio composition and itsoccupancy of brain dopamine D2 receptors in healthy subjects using PET.

FIG. 6A presents data from the human clinical study (n=11) on thebinding to dopamine D2 receptors of the 85:15 ratio by weight percentage(w/w %) composition of (R)-amisulpride to (S)-amisulpride.

The human clinical trials of Examples 4-6 determined that increasing theratio of (R)-amisulpride relative to (S)-amisulpride changes thepharmacology of the unequal enantiomeric mixtures of amisulpride.Increasing the ratio of (R)-amisulpride relative to (S)-amisulpridechanged the balance of clinically-meaningful pharmacological activitiesfrom a dopamine D₂ receptor-dominating compound (the racemate) into a5-HT₇ pharmacodynamic-preferring composition.

The human clinical trials of Examples 5 and 6 unexpectedly discoveredthat given the declining plasma concentrations, stable D2 brainoccupancies were nevertheless observed out to 27 hours. In comparison,another rapidly eliminated D2 antagonist, quetiapine, has an eliminationhalf-life of about 7 hours and a D2 occupancy trough associated with theplasma concentration trough. (C. L. Delaney and C. B. Nemeroff, Clin.Pharmokinetics, 40 (7), 509-522 (2001); D. C. Mamo et al., J. Clin.Psychiatry, 69:1, 81-86 (2008)). Thus, it was surprisingly discoveredthat after 27 hours (over two full half-lives) the brain D2 occupancy inthe study for subjects administered an 85:15 mixture((R)-amisulpride:(S)-amisulpride) was still as high as it was at 8 hourspost dose.

The human clinical trials of Examples 4 and 5 also determined that the85:15 fixed ratio composition of (R)-amisulpride to (S)-amisulprideprovided the highest ratio of overlap of 5-HT7 effect (required tosustain a decrease in the amount of REM sleep between about 20 to about45 minutes, a latency to REM sleep of about 15 minutes, and a decreasein total REM sleep time relative to total sleep time of about 5%) with aD2 occupancy in the range between about 30% to about 50%.

FIGS. 6B and 6C summarize data from Examples 4-6 and illustrates thesubstantial overlap of the 5-HT₇ effect with 30% to 50% D₂ receptoroccupancy that may be achieved with administration of an 85:15 ratio byweight percentage (w/w %) mixture of (R)-amisulpride to (S)-amisulpride.FIG. 6B presents data on a racemic (50:50 ratio by weight percentagemixture of (R)-amisulpride to (S)-amisulpride) and FIG. 6C presents dataon an 85:15 ratio by weight percentage mixture of (R)-amisulpride to(S)-amisulpride.

FIG. 6B illustrates that the desired therapeutic effect attributable toserotonin 5-HT7 antagonism cannot be achieved with a racemic mixturewithout also resulting in D2 occupancy levels associate with EPS sideeffects. For example, even for lower 5-HT7 antagonism effects (e.g.,decrease in the amount of REM sleep by about 20) the D2 occupancy isabout 78%, a level strongly associated with EPS related side effects.Accordingly, racemic amisulpride cannot provide the antidepressanteffect of (R)-(+)-amisulpride discovered by the present inventors atdosages that also have less than about 60% D2 receptor occupancy.Correspondingly, dosages of racemic amisulpride that provide less thanabout 60% D2 receptor occupancy cannot provide sufficient serotonergicantagonism to provide the discovered antidepressant effect of(R)-(+)-amisulpride.

FIG. 6C illustrates a R:S enantiomeric ratio (85:15) ratio discovered bythe present inventors that provides both a desirable D2 dopamine effectat D2 occupancy levels not generally associated with EPS side effectsand a desirable serotonergic antagonism that provides the discoveredantidepressant effect of (R)-(+)-amisulpride. In various embodiments,the present inventors have discovered that between about 200 mg andabout 700 mg of total amisulpride, in a R:S ratio of 85:15 by weight,can provide a therapeutic D2 dopamine effect and a therapeuticserotonergic antagonism whilst decreasing and/or eliminating negativeside effects generally associated with high D2 occupancy.

From another perspective, FIGS. 15A, 15B, and 15C present analyticaldata on the effects of mixtures of amisulpride.

FIG. 15A presents data from human clinical studies on the effects of(R)-amisulpride (dark circles) on 5-HT₇ (decrease in the amount of REMsleep minutes) from Example 5, where the x-axis in the top graph is50:50 racemic amisulpride, and the x-axis in the bottom graph is 85:15ratio by weight percentage (w/w %) of R:S-amisulpride. The mgdesignations indicate the amount of the indicted enantiomer in theracemic mixture (top graph) and in the 85:15 ratio of R:S amisulpride.The amount of total amisulpride is reduced by changing the mixture ofR:S amisulpride. For example, in a racemic mixture, it would require 680mg of amisulpride in order to administer 340 mg of (R)-amisulpride. Incontrast, in an 85:15 ratio of R:S, 400 mg of amisulpride would provide340 mg of (R)-amisulpride.

FIG. 15B presents data from human clinical studies on the binding todopamine D2 receptors of (S)-amisulpride and an 85:15 ratio by weightpercentage (w/w %) of (R)-amisulpride to (S)-amisulpride. The x-axis inthe top graph is 50:50 racemic amisulpride. The mg designations indicatethe amount of the indicted enantiomer in the racemic mixture (topgraph). The top graph shows the effect of (S)-amisulpride (grey circles)has on D2 occupancy based on data from Example 4. In the top graph,about 30-50% of D2 occupancy is associated with about 77-184 mg ofracemic amisulpride, which corresponds to about 39-92 mg of(S)-amisulpride and about 39-92 mg of (R)-amisulpride. The x-axis in thebottom graph is 85:15 ratio of (R)-amisulpride to (S)-amisulpride. Themg designations indicate the amount of the indicted enantiomer in the85:15 ratio of R:S-amisulpride (bottom graph). The bottom graph showsthe effects of (S)-amisulpride (grey circles) and 85:15 ratio (whitediamonds) have on D2 occupancy based on data from Example 4 and Example6, respectively. The bottom graph shows that about 30-50% of D2occupancy is associated with about 257-614 mg of 85:15 ratio ofR:S-amisulpride, which corresponds to about 39-92 mg of (S)-amisulprideand about 218-522 mg of (R)-amisulpride. As readily apparent, the ratioof 85:15 R:S amisulpride provides a greater amount of R enantiomer thanS enantiomer.

FIG. 15C illustrates the substantial overlap of the 5-HT₇ effect with30% to 50% D₂ receptor occupancy that can be achieved withadministration of an 85:15 ratio of (R)-amisulpride to (S)-amisulpride.The x-axis in the top graph is the total amount of racemic amisulpride.The mg designations indicate the amount of the indicted enantiomer inthe racemic mixture. The grey shaded circles are the data for(S)-amisulpride from Example 4, showing the effect of (S)-amisulpridehas on D2 occupancy. The dark circles are the data for (R)-amisulpridefrom Example 5, showing the effect of (R)-amisulpride has on 5-HT7. Thex-axis in the bottom graph is the total amount of 85:15 ratio R:Samisulpride. The mg designations indicate the amount of the indictedenantiomer in the 85:15 ratio mixture (bottom graph). The grey shadedcircles are the data for (S)-amisulpride from Example 4, showing theeffect of (S)-amisulpride has on D2 occupancy. The dark circles are thedata for (R)-amisulpride from Example 5, showing the effect of(R)-amisulpride has on 5-HT₇. The white diamonds are data for the 85:15ratio R:S amisulpride from Example 6 (D2 occupancy).

As can be seen in FIG. 15C top graph, about 30-50% of D₂ occupancy isassociated with about 77-184 mg of racemic amisulpride, whichcorresponds to about 39-92 mg of (S)-amisulpride and about 39-92 mg of(R)-amisulpride (top graph). However, about 39-92 mg of (R)-amisulprideis not enough to achieve sufficient 5-HT₇ effect associated with thediscovered antidepressant activity. As shown on the dotted line andsolid black circles, 340 mg of (R)-amisulpride provides a decrease inREM sleep by about 20 minutes. 340 mg of (R)-amisulpride projected ontothe curve of racemic amisulpride (solid line) shows that the D2occupancy is 78%, which is in the range that is associated with sideeffects. Similarly, as shown on the dotted line and solid black circles,600 mg of (R)-amisulpride provides a decrease in REM sleep by about 30minutes. 600 mg of (R)-amisulpride projected onto the curve of racemicamisulpride (solid line) shows that the D2 occupancy is 86%, which abovethe occupancy level associated with significant dopamine D2 receptoroccupancy side effects.

Also, as shown in FIG. 15C bottom graph, about 275-614 mg of amisulpride(85:15 ratio of R:S) provides about 30-50% D₂ antagonism. The amount ofabout 257-614 mg (85:15 ratio of R:S) corresponds to about 39-92 mg(S)-amisulpride and about 218-522 mg (R)-amisulpride. The ratio of 85:15R:S amisulpride provides a greater amount of R enantiomer than the Senantiomer. This in turn allows for administration of greater amount of(R)-amisulpride than (S)-amisulpride in order to avoid side effectsassociated with D₂ occupancy while, as the inventors have discovered,still providing sufficient 5-HT7 effect. A racemic mixture ofamisulpride does not and cannot provide this unequal amount of (R) and(S)-amisulpride. The inventors have thus discovered that the ratio of85:15 R:S amisulpride provides a substantial overlap in the doseintervals of the two enantiomers that achieves their respective D2 and5-HT7 effects.

The compounds disclosed herein can include isotopes. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. In someembodiments, one or more atoms of the compounds can be replaced orsubstituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, one or more hydrogen atoms in a compoundof the present disclosure can be replaced or substituted by deuterium.

As used herein, and unless otherwise specified, the term “about”, whenused in connection with a numeric value or range of values may vary by5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or0.1% of the recited value or range of values. In some embodiments, thenumeric value or range of values vary by 5%.

Crystal Forms of Enantiomeric Amisulpride

In various embodiments, the present inventions make use of a distinctpolymorph of (R)-(+)-amisulpride, (S)-(−)-amisulpride, or both, invarious embodiments of the compositions, formulations, methods andmedicaments of the present inventions.

Polymorphism is the ability of an element or compound to crystallizeinto distinct crystalline phases. Although the term polymorph impliesmore than one morphology, the term is still used in the art, and herein,to refer to a crystalline structure of a compound as a polymorph evenwhen only one crystalline phase is currently known. Thus, polymorphs aredistinct solids sharing the same molecular formula as other polymorphsand the amorphous (non-crystalline) phase, however since the propertiesof any solid depends on its structure, polymorphs often exhibit physicalproperties distinct from each other and the amorphous phase, such asdifferent solubility profiles, different melting points, differentdissolution profiles, different thermal stability, differentphotostability, different hygroscopic properties, different shelf life,different suspension properties and different physiological absorptionrates. Inclusion of a solvent in the crystalline solid leads tosolvates, and in the case of water as a solvent, hydrates, often leadsto a distinct crystalline form with one or more physical properties thatare distinctly different from the non-solvated and non-hydrated (e.g.,free base) crystalline form. In various embodiments, Form A and A′ areanhydrous, e.g., substantially free of water and solvent.

As used herein, the term “polymorph” refers to different crystalstructures achieved by a particular chemical entity. As used herein, theterm “solvate” refers to a crystal form where a stoichiometric ornon-stoichiometric amount of solvent, or mixture of solvents, isincorporated into the crystal structure. Similarly, the term “hydrate”refers to a crystal form where a stoichiometric or non-stoichiometricamount of water is incorporated into the crystal structure.

In various embodiments of the compositions of the present inventions,(R)-amisulpride and (S)-amisulpride are independently provided in a freebase crystal form, and thus without any water or solvent incorporatedinto the crystal structure. It has been found that (R)-amisulpride and(S)-amisulpride can exist in at least one such free base crystal form,or polymorph, which is referred to herein as Form A for crystalline(R)-amisulpride, and Form A′ for crystalline (S)-amisulpride.

Form A and Form A′ are described herein, and further described in U.S.Provisional Patent Application Ser. No. 62/594,851 filedcontemporaneously with the present application; and which is herebyincorporated herein by reference in its entirety. Form A and Form A′ arealso described U.S. Provisional Patent Application Ser. No. 62/594,851filed on Mar. 30, 2018, and is hereby incorporated herein by referencein its entirety.

Crystal forms of amisulpride, enantiomeric amisulpride, and crystallineforms of their salts, hydrates and solvates, including those of thepresent inventions, may be characterized and differentiated using anumber of conventional analytical techniques, including but not limitedto X-ray powder diffraction (XRPD) patterns, nuclear magnetic resonance(NMR) spectra, Raman spectra, Infrared (IR) absorption spectra, dynamicvapor sorption (DVS), Differential Scanning calorimetry (DSC), andmelting point. Chemical purity may be characterized using a number ofconventional analytical techniques, including but not limited to highperformance liquid chromatography (HPLC) and gas chromatography (GC).For example, one skilled in the art could use a reverse phase gradientHPLC method or a reverse phase isocratic HPLC method to determineorganic impurities, a headspace GC method to determine residualsolvents, coulometric titration (Karl Fischer) to determine watercontent, and a reverse phase isocratic HPLC method or a polar organicphase isocratic HPLC method to determine the amount of drug product in asample. Chiral purity (also known as enantiomeric purity) may becharacterized using a number of conventional analytical techniques,including but not limited to chiral high performance liquidchromatography (HPLC).

In various embodiments, the crystal forms of racemic amisulpride,enantiomeric amisulpride, and enantiomeric amisulpride solvates arecharacterized by X-ray powder diffraction (XRPD). XRPD is a technique ofcharacterizing a powdered sample of a material by measuring thediffraction of X-rays by the material. The result of an XRPD experimentis a diffraction pattern. Each crystalline solid produces a distinctivediffraction pattern containing sharp peaks as a function of thescattering angle 2θ (2-theta). Both the positions (corresponding tolattice spacing) and the relative intensity of the peaks in adiffraction pattern are indicative of a particular phase and material.This provides a “fingerprint” for comparison to other materials. Incontrast to a crystalline pattern comprising a series of sharp peaks,amorphous materials (liquids, glasses etc.) produce a broad backgroundsignal in a diffraction pattern.

It is to be understood that the apparatus employed, humidity,temperature, orientation of the powder crystals, and other parametersinvolved in obtaining an XRPD pattern may cause some variability in theappearance, intensities, and positions of the lines in the diffractionpattern. An XRPD pattern that is “substantially in accord with” that ofa Figure provided herein (e.g., FIG. 7B) is an XRPD pattern that wouldbe considered by one skilled in the art to represent a compoundpossessing the same crystal form as the compound that provided the XRPDpattern of that Figure. That is, the XRPD pattern may be identical tothat of the Figure, or more likely it may be somewhat different. Such anXRPD pattern may not necessarily show each of the lines of thediffraction patterns presented herein, and/or may show a slight changein appearance, intensity, or a shift in position of said lines resultingfrom differences in the conditions involved in obtaining the data. Aperson skilled in the art is capable of determining if a sample of acrystalline compound has the same form as, or a different form from, aform disclosed herein by comparison of their XRPD patterns.

For example, one skilled in the art could use a chiral HPLC method (e.g.polar organic mode isocratic HPLC) to determine the enantiomericidentity of an amisulpride sample and if, for example, the sample isidentified as (R)-amisulpride, one skilled in the art can overlay anXRPD pattern of the amisulpride sample with FIG. 7B and/or FIG. 8B, andusing expertise and knowledge in the art, readily determine whether theXRPD pattern of the sample is substantially in accordance with the XRPDpattern of crystalline (R)-amisulpride of Form A presented in FIG. 7B.If, for example, HPLC identifies the sample as being (R)-amisulpride andthe sample XRPD pattern is substantially in accord with FIG. 7B, thesample can be readily and accurately identified as (R)-amisulpride ofForm A.

In various embodiments, the crystal forms of racemic amisulpride,enantiomeric amisulpride, and enantiomeric amisulpride solvates arecharacterized by melting point. Melting points were determined byconventional methods such as capillary tube and may exhibit a range overwhich complete melting occurs, or in the case of a single number, a meltpoint of that temperature±1° C.

In various embodiments, the crystal forms of racemic amisulpride,enantiomeric amisulpride, and enantiomeric amisulpride solvates arecharacterized by differential scanning calorimetry (DSC). DSC is athermoanalytical technique in which the difference in the amount of heatrequired to increase the temperature of a sample and a reference ismeasured as a function of temperature. Both the sample and reference aremaintained at substantially the same temperature throughout theexperiment. The result of a DSC experiment is a curve of heat flowversus temperature, called a DSC thermogram.

In various embodiments, the hygroscopicity of crystal forms of racemicamisulpride, enantiomeric amisulpride, and enantiomeric amisulpridesolvates are characterized by dynamic vapor sorption (DVS). DVS is agravimetric technique that measures how much of a solvent is absorbed bya sample by varying the vapor concentration surrounding the sample(e.g., relative humidity) and measuring the change in mass. In thepresent application, DVS is used to generate water sorption isotherms,which represent the equilibrium amount of vapor sorbed as a function ofsteady state relative vapor pressure at a constant temperature.

As used herein, the term “substantially non-hygroscopic” refers to acompound exhibiting less than a 1% maximum mass change in water sorptionisotherms, at 25° C. scanned over 0 to 95% relative humidity, asmeasured by dynamic vapor sorption (DVS).

In various embodiments, the compositions of the present inventions usenew crystalline forms of enantiomeric amisulpride, Form A and Form A′.Forms A and A′ have been found to be a distinct polymorph, differentfrom the crystalline form of a racemic amisulpride, having a distinctlydifferent structure and XRPD pattern, as well as physical properties.Table 7 compares various properties and data on Form A crystals of(R)-amisulpride and Form A′ crystals of (S)-amisulpride where the Figurereferences are to figures in the present application. The SpecificRotation data was obtained by polarimetry, the subject compound wasdissolved in methanol at nominal concentration of c=1 using the 589 nm(Sodium Line). It is to be understood that upon dissolution of thecompound it is no longer of a crystalline form, thus one of ordinaryskill in the art will understand that the specific rotation in Table 7refers to that of the non-crystalline compound.

TABLE 7 Compound (R)-amisulpride (S)-amisulpride Physical Property FormA Form A′ # of Solid Phases 1 1 Melting Point, ° C. 102 102 DSCThermograph FIG. 7A FIG. 8A XRPD Pattern FIG. 7B FIG. 8B MicrographImage FIG. 7C FIG. 8C Specific Rotation [α]²⁰ _(D) = 5.1 · 10¹ [α]²⁰_(D) = −5.0 · 10¹ (MeOH, c = 1) (MeOH, c = 1) Solubility (mg/mL): Water2 2 (solution pH) (10.2) (10.3) 0.05 M Acetate Buffer >100 >100(solution pH) (4.5) (4.5) Ethyl Acetate 3.9 3.9 Acetone/MtBE 1:4 8 8Acetone/MtBE 1:9 2 2 Simulated Gastric Fluid (no >100 >100 enzyme) (pHadjusted to 1.1) (pH adjusted to 1.2) Simulated Intestinal Fluid(no >100 >100 enzyme) (pH adjusted to 6.7) (pH adjusted to 6.9)

In various embodiments, Form A is a crystalline form of (R)-amisulpridecharacterized by an XRPD pattern comprising peaks, in terms of 2-theta,at 7.0±0.2°, 9.7±0.2°, and 19.4±0.2°. In various embodiments, thecrystalline form of (R)-amisulpride is characterized by three or morepeaks in its XRPD pattern selected from those at 7.0±0.2°, 9.7±0.2°,15.4±0.2°, 19.4±0.2°, 20.1±0.2°, 21.0±0.2°, 23.2±0.2°, and 29.3±0.2°, interms of 2-theta. In various embodiments, the crystalline form of(R)-amisulpride is characterized by an XRPD pattern substantially inaccord with FIG. 7B.

In various embodiments, the crystalline Form A of (R)-amisulpride ischaracterized by the following properties, an XRPD pattern comprisingpeaks, in terms of 2-theta, at 7.0±0.2°, 9.7±0.2°, and 19.4±0.2°, amelting point of 102±3° C., a chiral purity of greater than about 99%, achemical purity greater than about 99%, a residual solvent content ofless than about 1000 ppm, and is substantially non-hygroscopic.

In various embodiments, the crystalline Form A of (R)-amisulpride ischaracterized by the following properties, an XRPD pattern comprisingpeaks, in terms of 2-theta, at 7.0±0.2°, 9.7±0.2°, and 19.4±0.2° and oneor more of the following:

-   -   (a) the powder x-ray diffraction pattern further comprising        peaks, in terms of 2-theta, at 15.4±0.2° and 29.3±0.2°;    -   (b) the powder x-ray diffraction pattern further comprising        peaks, in terms of 2-theta, at 20.1±0.2°, 21.0±0.2°, and        23.2±0.2°;    -   (c) a melting point of 102±3° C.;    -   (d) a differential scanning calorimetry thermogram comprising a        peak at 101±3° C.;    -   (e) a differential scanning calorimetry thermogram substantially        in accord with FIG. 7A;    -   (f) a chiral purity of greater than about: (i) 90%, (ii)        95%, (iii) 97%, (iv) 99%, (v) 99.5%, (vi) 99.7%, or (vii) 99.9%;    -   (g) a chemical purity of greater than about: (i) 80%, (ii)        90%, (iii) 95%, (iv) 97%, (v) 99%, (vi) 99.5%, (vii) 99.7%,        or (viii) 99.9%;    -   (h) residual solvents present in an amount less than about: (i)        8000 ppm, (ii) 6000 ppm, (iii) 4000 ppm, (iv) 2000 ppm, (v) 1000        ppm, (vi) 800 ppm, or 500 ppm; and    -   (i) as measured by dynamic vapor sorption (DVS), at 25° C.        scanned over 0 to 95% relative humidity, a maximum mass change        in water sorption isotherms of less than about (i) 2%, (ii)        1%, (iii) 0.5%, or (iv) 0.4%.

In various embodiments, the crystalline Form A′ of (S)-amisulpride ischaracterized by an XRPD pattern comprising peaks, in terms of 2-theta,at 7.0±0.2°, 9.7±0.2°, and 19.4±0.2°. In various embodiments, thepresent inventions provide a crystalline form of (S)-amisulpridecharacterized by three or more peaks in its XRPD pattern selected fromthose at 7.0±0.2°, 9.7±0.2°, 15.4±0.2°, 19.4±0.2°, 20.1±0.2°, 21.0±0.2°,23.2±0.2°, and 29.3±0.2°, in terms of 2-theta. In various embodiments,the present inventions provide a crystalline form of (S)-amisulpridecharacterized by an XRPD pattern substantially in accord with FIG. 8B.

In various embodiments, the crystalline Form A′ of (S)-amisulpride ischaracterized by the following properties, an XRPD pattern comprisingpeaks, in terms of 2-theta, at 7.0±0.2°, 9.7±0.2°, and 19.4±0.2°, amelting point of 102±3° C., a chiral purity of greater than about 99%, achemical purity greater than about 99%, a residual solvent content ofless than about 1000 ppm, and is substantially non-hygroscopic.

In various embodiments, the crystalline Form A′ of (S)-amisulpride ischaracterized by the following properties, an XRPD pattern comprisingpeaks, in terms of 2-theta, at 7.0±0.2°, 9.7±0.2°, and 19.4±0.2° and twoor more of the following:

-   -   (a) the powder x-ray diffraction pattern further comprising        peaks, in terms of 2-theta, at 15.4±0.2° and 29.3±0.2°;    -   (b) the powder x-ray diffraction pattern further comprising        peaks, in terms of 2-theta, at 20.1±0.2°, 21.0±0.2°, and        23.2±0.2°;    -   (c) a melting point of 102±3° C.;    -   (d) a differential scanning calorimetry thermogram comprising a        peak at 101±3° C.;    -   (e) a differential scanning calorimetry thermogram substantially        in accord with FIG. 8A;    -   (f) a chiral purity of greater than about: (i) 90%, (ii)        95%, (iii) 97%, (iv) 99%, (v) 99.5%, (vi) 99.7%, or (vii) 99.9%;    -   (g) a chemical purity of greater than about: (i) 80%, (ii)        90%, (iii) 95%, (iv) 97%, (v) 99%, (vi) 99.5%, (vii) 99.7%,        or (viii) 99.9%;    -   (h) residual solvents present in an amount less than about: (i)        8000 ppm, (ii) 6000 ppm, (iii) 4000 ppm, (iv) 2000 ppm, (v) 1000        ppm, (vi) 800 ppm, or 500 ppm; and    -   (i) as measured by dynamic vapor sorption (DVS), at 25° C.        scanned over 0 to 95% relative humidity, a maximum mass change        in water sorption isotherms of less than about (i) 2%, (ii)        1%, (iii) 0.5%, or (iv) 0.4%.

In various embodiments, crystalline enantiomeric amisulpride of Form Ais characterized at least in part by having an XRPD pattern comprisingpeaks, in terms of 2-theta, at 7.0±0.2°, 9.7±0.2°, and 19.4±0.2° and nothaving a peak, in terms of 2-theta, at 6.6±0.3° that has a heightgreater than about 5% of the highest of the peaks at 7.0±0.2°, 9.7±0.2°,and 19.4±0.2°.

In various embodiments, crystalline enantiomeric amisulpride of Form A′is characterized at least in part by having an XRPD pattern comprisingpeaks, in terms of 2-theta, at 7.0±0.2°, 9.7±0.2°, and 19.4±0.2° and nothaving a peak, in terms of 2-theta, at 6.6±0.3° that has a heightgreater than about 5% of the highest of the peaks at 7.0±0.2°, 9.7±0.2°,and 19.4±0.2°.

In various embodiments, XRPD information and patterns are used tocharacterize Forms A and A′. FIGS. 7B and 8B XRPD patterns for,respectively, (R)-amisulpride Form A and (S)-amisulpride Form A′. Tables8-11 present further information and details on XRPD patterns obtainedfor Forms A and A′.

The XRPD patterns of both (R)-amisulpride Form A (FIG. 7B) and(S)-amisulpride Form A′ (FIG. 8B) show prominent peaks, in terms of2-theta, at 7.0±0.2°, 9.7±0.2°, 15.4±0.2°, 19.4±0.2°, 20.1±0.2°,21.0±0.2°, 23.2±0.2°, and 29.3±0.2°.

In various embodiments, provided herein is a crystalline form of(R)-(+)-amisulpride characterized by a powder x-ray diffraction patterncomprising peaks, in terms of 2-theta, at 7.0±0.2°, 9.7±0.2°, and15.4±0.2°. In some embodiment, the crystalline form of(R)-(+)-amisulpride is further characterized by the powder x-raydiffraction pattern further comprising peaks, in terms of 2-theta, at9.3±0.2°, and 19.4±0.2°. In some embodiment, the crystalline form of(R)-(+)-amisulpride is further characterized by the powder x-raydiffraction pattern further comprising peaks, in terms of 2-theta, at14.9±0.2°, 16.9±0.2°, and 20.1±0.2°. In some embodiment, the crystallineform of (R)-(+)-amisulpride is further characterized by the powder x-raydiffraction pattern further comprising peaks, in terms of 2-theta, at19.0±0.2°, 21.0±0.2°, and 23.2±0.2°.

In various embodiments, provided herein is a crystalline form of(S)-(−)-amisulpride characterized by a powder x-ray diffraction patterncomprising peaks, in terms of 2-theta, at 7.0±0.2°, 9.7±0.2°, and15.4±0.2°. In some embodiments, the crystalline form of(S)-(−)-amisulpride is further characterized by the powder x-raydiffraction pattern further comprising peaks, in terms of 2-theta, at9.3±0.2°, and 19.4±0.2°. In some embodiments, the crystalline form of(S)-(−)-amisulpride is further characterized by the powder x-raydiffraction pattern further comprising peaks, in terms of 2-theta, at14.9±0.2°, 16.9±0.2°, and 20.2±0.2°. In some embodiments, thecrystalline form of (S)-(−)-amisulpride is further characterized by thepowder x-ray diffraction pattern further comprising peaks, in terms of2-theta, at 19.1±0.2°, 21.0±0.2°, and 23.2±0.2°.

The DSC thermograms of FIGS. 7A and 8A were obtained using TAInstruments Q100 differential scanning calorimeter. Each sample washeated in a sealed pan under a 50 mL/min nitrogen purge at a heatingrate of 10° C./min, from a starting temperature of 25° C. up to a finaltemperature of 150° C. or 200° C.

The micrograph images of FIGS. 7C and 8C were obtained using the NikonMicrophot polarizing light microscope. Samples were prepared in IsoparG/3% Lecithin, and imaged using cross-polarized light with a quarterwave plate.

The XRPD patterns of FIGS. 7B and 8B were performed using a RigakuMiniFlex II Desktop X-Ray diffractometer using Cu radiation. The tubevoltage and amperage were set to 30 kV and 15 mA, respectively. Thescattering slit was fixed at 1.250 and the receiving slit was fixed at0.3 mm. Diffracted radiation was detected by a NaI scintillationdetector. A 0-20 continuous scan at 1.0°/min with a step size of0.02-0.05° from 3 to 45° 2θ was used. Data were collected and analyzedusing Jade 8.5.4. Each sample was prepared for analysis by placing it ina low background, round, 0.1 mm indent sample holder. In FIGS. 7B and8B, 2-Theta angles in degrees (x-axis) are plotted against peakintensity in terms of the count rate per second (y-axis).

Crystals of (R)-Amisulpride Form A

For single crystal structure determination, a colorless needle havingapproximate dimensions of 0.25×0.04×0.02 mm³, was mounted on a polymerloop in random orientation. Preliminary examination and data collectionwere performed on a Rigaku SuperNova diffractometer, equipped with acopper anode microfocus sealed X-ray tube (Cu Kα λ=1.54184 Å) and aDectris Pilatus3 R 200K hybrid pixel array detector. Cell constants andan orientation matrix for data collection were obtained fromleast-squares refinement using the setting angles of 16528 reflectionsin the range 3.5080°<θ<77.2950°. The data was collected to a maximumdiffraction angle (2θ) of 155.296°, at a temperature of 100 K. A totalof 35826 reflections were collected, of which 12849 were unique. Lorentzand polarization corrections were applied to the data. The linearabsorption coefficient is 1.728 mm⁻¹ for Cu Kα radiation. An empiricalabsorption correction using CRYSALISPRO was applied (CrysAlisPro1.171.38.41r (Rigaku Oxford Diffraction, 2015). Transmissioncoefficients ranged from 0.659 to 1.000. Intensities of equivalentreflections were averaged. The agreement factor for the averaging was5.72% based on intensity.

A calculated XRPD pattern was generated for Cu radiation using MERCURYand the atomic coordinates, space group, and unit cell parameters fromthe single crystal structure (Macrae, C. F. et a., J. J. Appl. Cryst.,2006, 39, 453-457). It is to be understood that because the singlecrystal data are collected at low temperatures (100 K), peak shifts maybe evident between the pattern calculated from low temperature data androom temperature experimental powder diffraction patterns, particularlyat high diffraction angles. FIG. 16 shows the calculated XRPD pattern ofForm A.

In various embodiments, the crystal system of (R)-amisulpride Form Acrystals is triclinic and the space group is P1. Referring to FIG. 7C,by microscopy the solids consisted of birefringent spherulites of longneedles. Further details of the crystal data and crystallographic datacollection parameters are summarized in Table 8 and a listing of thepeaks of the experimental XRPD of FIG. 7B are listed in Table 9. Thecalculated XRPD pattern of Form A is shown in FIG. 16.

In some embodiment, the crystalline form of (R)-(+)-amisulpride ischaracterized by single crystal x-ray diffraction having a P1 spacegroup and cell formula units (Z) of 4. In some embodiments, crystallineform of (R)-(+)-amisulpride has unit cell parameters: a is about 12.3 Å,b is about 12.8 Å, c is about 14.1 Å, α is about 64.0°, β is about73.4°, and γ is about 75.9°.

TABLE 8 (R)-amisulpride Form A Single Crystal Data and Data CollectionParameters Empirical formula C₁₇H₂₇N₃O₄S Molecular weight (g mol⁻¹)369.47 Temperature (K) 100 Wavelength (Å) 1.54184 Crystal systemtriclinic Space group P1 Unit cell parameters a = 12.3348 (4) Å α =64.033 (4)° b = 12.8343 (6) Å β = 73.431 (3)° c = 14.1403 (6) Å γ =75.881 (3)° Unit cell volume (Å³) 1910.47 (15) Cell formula units, Z 4Calculated density (g cm⁻³) 1.285 Absorption coefficient (mm⁻¹) 1.728 F(000) 792 Crystal size (mm³) 0.25 × 0.04 × 0.02 Reflections used forcell measurement 16528 ϑ range for cell measurement 3.5080°-77.2950°Total reflections collected 35826 Index ranges −15 ≤ h ≤ 15; −16 ≤ k ≤16; −17 ≤ l ≤ 17 ϑ range for data collection ϑ_(min) = 3.552°, ϑ_(max) =77.648° Completeness to θ_(max) 97.6% Completeness to θ_(full) = 67.684°99.8% Absorption correction multi-scan Transmission coefficient range0.659-1.000 Refinement method full matrix least-squares on F²Independent reflections 12849 [R_(int) = 0.0572, R_(σ) = 0.0533]Reflections [l>2σ(l)] 11460 Reflections/restraints/parameters12849/3/954 Goodness-of-fit on F² S = 1.02 Final residuals [I>2σ(I)] R =0.0607, R_(w) = 0.1675 Final residuals [all reflections] R = 0.0658,R_(w) = 0.1739 Largest diff. peak and hole (e Å⁻³) 0.640, −0.670Max/mean shift/standard uncertainty 0.000/0.000 Absolute structuredetermination Flack parameter: 0.009 (18) Hooft parameter: 0.007 (12)Friedel coverage: 60.2%

TABLE 9 (R)-amisulpride Form A XRPD (FIG. 7B) Peak List 2-Theta RelativeHeight 7.00 75 7.42 1.6 9.34 26.9 9.72 68.3 9.95 1.5 11.00 6.7 11.66 1.212.72 2.3 13.26 11.3 13.90 5.2 14.41 4.8 14.72 13.5 14.90 31 15.40 10015.94 4 16.64 7.9 16.92 28 17.44 14.8 17.70 4 18.66 7.5 19.04 29.3 19.4287 20.12 63.7 20.98 34.8 21.62 3.5 21.88 7.8 22.32 3.8 22.61 2.5 23.2289.3 24.34 8.1 24.80 8.7 25.26 3 25.56 17 25.78 4.3 26.20 3.2 26.68 15.827.10 11.3 28.12 3.5 28.28 2.6 28.82 5.2 29.26 42.2 29.56 5.9 29.76 3.730.32 1.9 30.92 1.7 31.02 2.6 31.70 4.3 31.94 3.8 32.26 2.2 32.84 8.933.22 2.7 34.16 2.7 34.55 2.2 34.97 1.7 35.24 1.1 35.48 0.9 35.76 2.937.00 1.9 37.44 1.3 38.58 3.2 38.88 3.4 39.50 1.6 39.76 2.1 40.38 2.540.80 3.7 41.39 1.4 41.68 1.5 42.68 3.7 43.28 2.8 43.52 4.7

Crystals of (S)-Amisulpride Form A′

For single crystal structure determination, a colorless needle havingapproximate dimensions of 0.20×0.04×0.02 mm³, was mounted on a polymerloop in random orientation. Preliminary examination and data collectionwere performed on a Rigaku SuperNova diffractometer, equipped with acopper anode microfocus sealed X-ray tube (Cu Kα λ=1.54184 Å) and aDectris Pilatus3 R 200K hybrid pixel array detector. Cell constants andan orientation matrix for data collection were obtained fromleast-squares refinement using the setting angles of 14943 reflectionsin the range 3.5170°<θ<77.9740°. The data was collected to a maximumdiffraction angle (2θ) of 156.71°, at a temperature of 100 K. A total of36278 reflections were collected, of which 12840 were unique. Lorentzand polarization corrections were applied to the data. The linearabsorption coefficient is 1.728 mm-1 for Cu Kα radiation. An empiricalabsorption correction using CRYSALISPRO was applied (CrysAlisPro1.171.38.41r (Rigaku Oxford Diffraction, 2015). Transmissioncoefficients ranged from 0.791 to 1.000. Intensities of equivalentreflections were averaged. The agreement factor for the averaging was5.83% based on intensity.

A calculated XRPD pattern was generated for Cu radiation using MERCURYand the atomic coordinates, space group, and unit cell parameters fromthe single crystal structure (Macrae, C. F. et a., J. J. Appl. Cryst.,2006, 39, 453-457). It is to be understood that because the singlecrystal data are collected at low temperatures (100 K), peak shifts maybe evident between the pattern calculated from low temperature data androom temperature experimental powder diffraction patterns, particularlyat high diffraction angles. FIG. 17 shows the calculated XRPD pattern ofForm A′.

In various embodiments, the crystal system of (S)-amisulpride Form A′crystals is triclinic and the space group is P1. Referring to FIG. 8C,by microscopy the solids consisted of birefringent spherulites of longneedles. Further details of the crystal data and crystallographic datacollection parameters are summarized in Table 10 and a listing of thepeaks of the experimental XRPD of FIG. 8B are listed in Table 11. Thecalculated XRPD pattern of Form A′ is shown in FIG. 17.

In some embodiments, the crystalline form of (S)-(−)-amisulpride ischaracterized by single crystal x-ray diffraction having a P1 spacegroup and cell formula units (Z) of 4. In some embodiments, thecrystalline form of (S)-(−)-amisulpride has unit cell parameters: a isabout 12.4 Å, b is about 12.8 Å, c is about 14.1 Å, α is about 64.2°, βis about 73.6°, and γ is about 75.8°.

TABLE 10 (S)-amisulpride Form A′ Single Crystal Data and Data CollectionParameters Empirical formula C₁₇H₂₇N₃O₄S Formula weight (g mol⁻¹) 369.47Temperature (K) 100 Wavelength (Å) 1.54184 Crystal system triclinicSpace group P1 Unit cell parameters a = 12.3795 (4) Å α = 64.246 (3)° b= 12.7526 (4) Å β = 73.598 (3)° c = 14.1438 (4) Å γ = 75.797 (3)° Unitcell volume (Å³) 1909.71 (11) Cell formula units, Z 4 Calculated density(g cm⁻³) 1.285 Absorption coefficient (mm⁻¹) 1.728 F (000) 792 Crystalsize (mm³) 0.2 × 0.04 × 0.02 Reflections used for cell measurement 14943ϑ range for cell measurement 3.5170°-77.9740° Total reflectionscollected 36278 Index ranges −15 ≤ h ≤ 14; −16 ≤ k ≤ 16; −17 ≤ l ≤ 17 ϑrange for data collection ϑ_(min) = 3.542°, ϑ_(max) = 78.355°Completeness to θ_(max) 97.6% Completeness to θ_(full) = 67.684° 99.9%Absorption correction multi-scan Transmission coefficient range0.791-1.000 Refinement method full matrix least-squares on F²Independent reflections 12840 [R_(int) = 0.0583, R_(σ) = 0.0539]Reflections [l>2σ(l)] 11066 Reflections/restraints/parameters12840/3/956 Goodness-of-fit on F² S = 1.08 Final residuals [I>2σ(I)] R =0.0613, R_(w) = 0.1732 Final residuals [all reflections] R = 0.0694,R_(w) = 0.1817 Largest diff. peak and hole (e Å⁻³) 0.470, −0.468Max/mean shift/standard uncertainty 0.000/0.000 Absolute structuredetermination Flack parameter: 0.008 (18) Hooft parameter: 0.019 (12)Friedel coverage: 58.8%

TABLE 11 (S)-amisulpride Form A′ XRPD (FIG. 8B) Peak List 2-ThetaRelative Height 7.02 100 9.34 28 9.74 62 11.05 5.6 13.28 15.2 13.94 7.814.92 20 15.42 66.2 16.90 23.9 17.44 8.9 18.68 7.4 19.08 34.2 19.44 74.420.16 70 21.00 41.2 21.9 12 22.36 3.1 23.20 72.1 24.34 5.7 24.87 7 25.6016.9 25.84 6.2 26.17 2.3 26.70 14.8 27.12 12.1 28.12 5.2 29.28 40.430.36 2.2 31.84 3.8 32.30 2.4 32.84 9 33.26 3.7 34.17 2.5 34.64 2 35.101.8 35.84 2.8 36.14 1.6 37.00 1.6 37.48 2.1 38.60 4.8 38.94 5.2 39.521.6 39.75 2.1 40.38 4.1 40.76 4.2 41.48 1.8 42.76 3.6 43.50 5.7 44.121.1

In various embodiments, the crystalline Form A of (R)-amisulpride ischaracterized by an XRPD pattern comprising peaks, in terms of 2-theta,at two or more of 7.0±0.2°, 9.7±0.2°, and 19.4±0.2°, and a DSCthermogram having a peak at 101±3° C. In various preferred embodiments,the DSC thermogram has a single peak at 101±3° C.

In various embodiments, the a crystalline Form A of (R)-amisulpride ischaracterized by an XRPD pattern comprising peaks, in terms of 2-theta,at two or more of 7.0±0.2°, 9.7±0.2°, and 19.4±0.2°, and a differentialscanning calorimetry thermogram substantially in accord with FIG. 7A.

In various embodiments, the crystalline Form A′ of (S)-amisulpride ischaracterized by an XRPD pattern comprising peaks, in terms of 2-theta,at two or more of 7.0±0.2°, 9.7±0.2°, and 19.4±0.2°, and a DSCthermogram having a peak at 101±3° C. In various preferred embodiments,the DSC thermogram has a single peak at 101±3° C.

In various embodiments, the crystalline Form A′ of (S)-amisulpride ischaracterized by an XRPD pattern comprising peaks, in terms of 2-theta,at two or more of 7.0±0.2°, 9.7±0.2°, and 19.4±0.2°, and a differentialscanning calorimetry thermogram substantially in accord with FIG. 8A.

In various embodiments, the crystalline Forms A and A′ of enantiomericamisulpride is substantially non-hygroscopic. In various embodiments,crystalline (R)-amisulpride of Form A has a maximum mass change of lessthan about 2%, less than about 1%, or less than about 0.5%, in watersorption isotherms as measured by dynamic vapor sorption (DVS), at 25°C. scanned over 0 to 95% relative humidity. In various embodiments,crystalline (S)-amisulpride of Form A′ has a maximum mass change of lessthan about 2%, less than about 1%, or less than about 0.5%, in watersorption isotherms as measured by dynamic vapor sorption (DVS), at 25°C. scanned over 0 to 95% relative humidity.

FIG. 8D shows a DVS water sorption isotherm for 19.077 mg of(S)-amisulpride crystal Form A′ and Table 12 lists the data plotted inFIG. 8D. As can be seen, crystalline (S)-amisulpride Form A′ issubstantially non-hygroscopic, exhibiting a maximum mass change of only0.35%.

TABLE 12 (S)-amisulpride Form A′ DVS Water Sorption Isotherm of FIG. 8DRelative Change Mass Humidity % (wt %) Time/step (min) 0 0.00 60.72 100.03 33.25 20 0.05 31.89 30 0.07 32.20 40 0.09 31.53 50 0.11 31.95 600.13 31.87 70 0.16 31.10 75 0.18 31.28 80 0.19 31.43 90 0.25 31.97 950.34 32.77 95 0.35 36.47 90 0.28 31.35 80 0.17 32.11 75 0.16 31.01 700.14 31.50 60 0.11 32.10 50 0.08 32.12 40 0.07 31.41 30 0.05 62.67 200.03 32.05 10 0.01 31.00 1 −0.01 32.02

In various aspects, provided are methods of making enantiomericamisulpride crystalline polymorphs of Form A and Form A′. Variousembodiments of the methods described below produce novel crystal formsand various embodiments of these methods are in themselves novel.

As used in the context of the methods of the present inventions, theterm “Form A” or “Form A′” refers to a method that produces acrystalline form of enantiomeric amisulpride having a powder x-raycrystal pattern comprising peaks, in terms of 2-theta, at least at7.0±0.2°, 9.7±0.2°, and 19.4±0.2°; and preferably with additional peaks,in terms of 2-theta, at two or more of: 15.4±0.2°, 20.1±0.2°, 21.0±0.2°,23.2±0.2°, and 29.3±0.2°; and in various preferred embodiments an powderx-ray crystal pattern substantially in accord with FIG. 7B, in the caseof (R)-amisulpride, and FIG. 8B in the case of (S)-amisulpride.

Producing high yields of a specific crystalline form, and thus highpurity of that crystalline form, is often limited by the formation ofamorphous products and other crystalline forms that may, for example, bekinetically favored. It has been discovered through experimentation thatmaking crystalline enantiomeric amisulpride is complicated by the factthat traditional methods result in non-crystalline (amorphous)enantiomeric amisulpride, including methods that produce crystallineracemic amisulpride.

It has been discovered that formation of certain enantiomericamisulpride solvates as intermediates followed by conversion to the freebase allows for isolation of a crystalline form of enantiomericamisulpride (having a powder x-ray crystal pattern comprising peaks, interms of 2-theta, at least at 7.0±0.2°, 9.7±0.2°, and 19.4±0.2°) that isgreater than 90% by weight, greater than 95% by weight, greater than 97%by weight, greater than 99% by weight; or greater than 99.5% by weightof the enantiomeric amisulpride starting material.

In various embodiments, methods of making crystalline enantiomericamisulpride, characterized by an XRPD pattern comprising peaks, in termsof 2-theta, at least at 7.0±0.2°, 9.7±0.2°, and 19.4±0.2°, comprise: (a)providing either (R)-amisulpride or (S)-amisulpride as a startingmaterial, where (R)-amisulpride is provided as the starting materialwhen crystalline (R)-amisulpride is the desired product and(S)-amisulpride is provided as the starting material when crystalline(S)-amisulpride is the desired product; (b) solvating the startingmaterial with a first solvent where the first solvent is a carbonylcontaining compound having 5 carbons or less; (c) freeing the solvatedstarting material from the first solvent by adding a second solventother than water to form a mixture with a starting material solubilityof less than about 20 wt/wt %; and then (d) isolating the crystallineform of the starting material having a powder x-ray crystal patterncomprising peaks, in terms of 2-theta, at least at 7.0±0.2°, 9.7±0.2°,and 19.4±0.2°.

In various embodiments, the methods start with the provision of either(R)-amisulpride or (S)-amisulpride to make, respectively, crystalline(R)-amisulpride or crystalline (S)-amisulpride. It is to be understoodthat there are many acceptable ways to separate the enantiomers ofamisulpride to provide an enantiomeric starting material for the methodsof the present inventions. Examples 7 and 9 provide an in situ methodfor making enantiomerically enriched amisulpride starting material.

It is to be understood that the enantiomeric amisulpride startingmaterials of the present invention are not necessarily crystalline, andoften are amorphous or a mixture of amorphous and crystalline form. Inaddition to separation of enantiomers from a racemic starting material,suitable enantiomeric starting materials for the methods of the presentinventions can also be directly synthesized.

It is to be understood that the ultimate chiral purity of thecrystalline form of the starting material is limited by the chiralpurity of the starting material. However, in various embodiments, it hasbeen found that the methods produce the crystalline form of the startingmaterial that has a chiral purity that is no less than the chiral purityof the starting material. Thus, in various embodiments, the presentmethods of making crystalline enantiomeric amisulpride (characterized byan XRPD pattern comprising peaks, in terms of 2-theta, at least at7.0±0.2°, 9.7±0.2°, and 19.4±0.2°) provide said crystalline enantiomericamisulpride having one or more of: a greater than about 90% chiralpurity where the starting material has a greater than about 90% chiralpurity; a greater than about 95% chiral purity where the startingmaterial has a greater than about 95% chiral purity; a greater thanabout 97% chiral purity where the starting material has a greater thanabout 97% chiral purity; a greater than about 99% chiral purity wherethe starting material has a greater than about 99% chiral purity.

It has been unexpectedly found that by proper selection of the firstsolvent, an intermediate solvate can be formed that upon subsequentconversion to the free base can provide an amisulpride product wheregreater than 90% by weight, greater than 95% by weight, greater than 97%by weight, greater than 99% by weight; or greater than 99.5% by weightof amisulpride product is in the form of crystalline enantiomericamisulpride of starting material, characterized by an XRPD patterncomprising peaks, in terms of 2-theta, at least at 7.0±0.2°, 9.7±0.2°,and 19.4±0.2°.

The first solvent is a carbonyl containing compound having 5 carbons orless. Preferably, the first solvent has a water content of less than 3%by weight, more preferably less than 1% by weight, and more preferablyless than 0.5% by weight. It has been found that excess water in thefirst solvent interferes with, and can even prohibit, propercrystallization. Examples of such larger carbonyl containing solventinclude cyclohexanone. In various embodiments, the first solvent is analdehyde, ketone or ester. In various embodiments, the first solvent isethyl acetate, propyl acetate, or methyl ethyl ketone; and in variouspreferred embodiments the first solvent is ethyl acetate.

In various embodiments, the step of solvating includes basifying; forexample, by addition of a basic aqueous solution. In variousembodiments, a basic solution sufficient to raise the pH to greater than9.5, preferably to about 10, and in various embodiments between about9.5 and about 11, is added. In various embodiments, aqueous solutions ofpotassium carbonate are employed. It is to be understood that a varietyof basic solutions can be used to basify including, but not limited to,potassium carbonate, sodium carbonate, sodium hydroxide, and the like.

In various embodiments, the solvating step comprises multipleseparations between any aqueous phase and organic phase of the solventsystem of the solvating step, as may result, for example, frombasifying; the desired products being preferentially partitioned intothe organic phase. In various embodiments, the aqueous/organic solventsystem is heated to 30-40° C. to facilitate separation.

In various embodiments, subsequent to basifying, the organic phase isconcentrated and a stoichiometric excess of the first solvent is addedone or more times to facilitate complete conversion to the solvate. Inaddition, in various embodiments, repeated concentration and addition ofthe first solvent facilitates producing a concentrated solvate solutionhaving less than about 1 wt % water, less than about 0.7 wt % water, orless than about 0.4 wt % water, as determined by Karl Fischer titration.

In various embodiments, the reaction mixture is seeded with the desiredcrystalline form, (for example, seeding with crystalline (S)-amisulprideof Form A′ where the desired product is crystalline (S)-amisulpride ofForm A′) prior to addition of the second solvent. In variousembodiments, the step of solvating includes formation of a slurry by,for example, seeding the reaction mixture the desired crystalline formand cooling the reaction mixture below about 40° C., in variousembodiments below about 30° C., and preferably below about 20° C.

Following formation of the enantiomeric starting material solvate,(i.e., (R)-amisulpride solvate with the first solvent or a(S)-amisulpride solvate with the first solvent) the solvate is freedfrom the enantiomeric starting material to form the free base of theenantiomeric starting material under conditions that allow for theisolation of crystalline enantiomeric amisulpride characterized by anXRPD pattern comprising peaks, in terms of 2-theta, at least at7.0±0.2°, 9.7±0.2°, and 19.4±0.2°. In various embodiments, the reactionmixture is seeded with the desired crystalline form, (for example,seeding with crystalline (S)-amisulpride of Form A′ where the desiredproduct is crystalline (S)-amisulpride of Form A′) prior to addition ofthe second solvent. In various embodiments, the step of freeingcomprises cooling the reaction mixture to below about 40° C.

As used herein, the term “solvating” refers to the combination of(R)-amisulpride or (S)-amisulpride with a solvent.

As used herein, the terms “isolating” and “freeing” refer to separatingthe desired product from the environment in which it was formed ordetected. For example, separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the desired product.

In various embodiments, a second solvent (other than water) is added toform a mixture with a starting material solubility of less than about 20wt/wt %; less than about 10 wt/wt %; or less than about 5 wt/wt %. Oneof skill in the art will understand that in various embodiments thesecond solvent can be considered an anti-solvent as it lowers thesolubility of the mixture with respect to the desired product. It is tobe understood that a variety of compounds can be used as a secondsolvent including, but not limited to, methyl t-butyl ether, toluene,heptane, isopropanol, and the like. In various embodiments the secondsolvent is methyl t-butyl ether (MtBE).

A variety of procedures can be used to isolate the desired enantiomericcrystalline form of the starting material. In various embodiments, thestep of isolating comprises one or more of: (a) adding an anti-solvent;(b) cooling the mixture to below about 30° C., and in variousembodiments between about 10° C. and about 20° C.; and (c) adding seedcrystal of the R-enantiomer or S-enantiomer. In various embodiments, thestep of isolating comprises adding an anti-solvent and/or cooling thereaction mixture. In various embodiments use is made of seed crystals ofthe crystalline formed desired, and seed crystals can be obtained by oneof skill in the art using the teachings provided herein.

For example, Example 11 teaches methods of producing crystalline(R)-amisulpride ethyl acetate solvate. The product of these examplesupon drying above about 30° C., desolvates and converts to crystals ofcrystalline (R)-amisulpride free base of Form A and amorphous.Similarly, for example, Example 13 teaches a method producingcrystalline (S)-amisulpride ethyl acetate solvate. The product of theseexamples upon drying above about 30° C., desolvates and converts tocrystals of crystalline (S)-amisulpride free base of Form A′ andamorphous. Although the fraction of the solvate that converts to Form Aor Form A′ in the above examples is low, it is sufficient for obtainingseed crystals.

In various embodiments, the step of isolating the crystalline formcomprises seeding the reaction mixture with the desired crystallineform, (for example, seeding with crystalline (S)-amisulpride of Form A′where the desired product is crystalline (S)-amisulpride of Form A′)prior to addition of the second solvent, and, in various embodiments, aslurry is then formed by cooling the reaction mixture below about 40°C., in various embodiments below about 30° C., and preferably belowabout 20° C.

In various embodiments, the step of isolating comprises filtering aslurry comprising the desired crystalline form of the enantiomericamisulpride free base, washing the solid residue with a solvent systemcomprising the second solvent and the first solvent, and drying theresidue. In various embodiments, the wt/wt ratio of the second solventto first solvent (second solvent:first solvent) is greater than about1:9, and in various embodiments between about 1:9 to about 4:1. Invarious embodiments where the second solvent is MtBE and the firstsolvent ethyl acetate, the MtBe:ethyl acetate ratio is preferably about3:1.

In various embodiments, the methods of the present inventions for makingcrystalline enantiomeric amisulpride, characterized by an XRPD patterncomprising peaks, in terms of 2-theta, at least at 7.0±0.2°, 9.7±0.2°,and 19.4±0.2°, comprise recrystallization. In the Examples, examplemethods that do not show a recrystallization step are noted as forming a“crude freebase,” however it is to be understood that this nomenclatureis used only for distinguishing the examples.

Recrystallization can be performed by a variety of techniques. Invarious embodiments, a step of recrystallization comprises (a)dissolving the crystalline enantiomeric amisulpride material in asolvent/anti-solvent solution; (b) cooling the solution comprising thestarting material and the solvent/anti-solvent solution; and (c) addinga seed crystal of the R or S enantiomeric amisulpride material. Invarious embodiments the step of dissolving includes heating of thesolution, to a temperature greater than 40° C. and below about 70° C.,and preferably between about 50° C. and about 65° C., and preferablyabout 60° C.

A variety of solvent/anti-solvent systems can be used. For example, invarious embodiments the solvent is acetone and the anti-solvent ismethyl t-butyl ether. In various embodiments, the solvent is isopropanol(IPA) and the anti-solvent is heptane. As understood by those of skillin the art, care must be taken in selection of the solvent/anti-solventsystem. For example, the inventors have found that in the IPA/heptanesystem a second liquid phase can form before seeding if the heptane toIPA ratio is greater than 1:1, that if a large excess of IPA is addedthe seeds will dissolve then crystallize upon addition of heptaneantisolvent and cooling, and that a preferred IPA:heptane:product ratiois 36:32:32.

Non-limiting examples of various embodiments of making crystallineenantiomeric amisulpride of Forms A and A′, or characterized by an XRPDpattern comprising peaks, in terms of 2-theta, at least at 7.0±0.2°,9.7±0.2°, and 19.4±0.2°, are further illustrated and described inExamples 7, 8, 9 and 10.

Aspects, embodiments, and features of the preparation andcharacterization of crystal forms of enantiomeric amisulpride may befurther understood from the following examples, which should not beconstrued as limiting the scope of the present inventions.

Crystal Forms of Enantiomeric Amisulpride Examples

It is to be understood that the enantiomeric amisulpride startingmaterials of the present invention are not necessarily crystalline, andoften are amorphous or a mixture of amorphous and crystalline form. Inaddition to separation of enantiomers from a racemic starting material,suitable enantiomeric starting materials for the methods of the presentinventions can also be directly synthesized.

Example 7: Synthesis ofR-4-Amino-N-[(t-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude freebase)

150 g of 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid and 2000 g ofacetone were placed in a flask. The solution was cooled to −9° C., and74.3 mL of ethyl chloroformate was added to the flask. Then 88.9 mL of4-methyl morpholine was added over 1 hour. 81.4 g of(R)-(1-ethylpyrrolidin-2-yl)methanamine was added and the mixturestirred for 16 h. The reaction was then concentrated and 800 g of waterand 300 g of ethyl acetate were added. The mixture was agitated and theorganic layer removed, which contained theR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidestarting material. The solution containing the starting material wasbasified by the addition of aqueous 20 wt % potassium carbonate and 2.5L of ethyl acetate was added. The aqueous layer was removed. The organiclayer was washed twice with water and concentrated to dryness. Then 800g of ethyl acetate was added and the mixture was concentrated. This wasrepeated once. The resulting oil was dissolved into 800 g of ethylacetate and concentrated to 600 mL. The solution was stirred at 30° C.and a slurry formed. The resulting slurry was cooled to 20° C. andagitated. 600 g of methyl t-butyl ether was added and the mixturestirred. The slurry was then filtered, washed with 3:1 wt/wt methylt-butyl ether:ethyl acetate and dried. 165 g ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidewas obtained as a crystalline solid.

Example 8: Recrystallization ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(freebase crystal Form A)

603.05 g ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(prepared substantially according to Example 7) and 500.3 g ofisopropanol were added to a flask with a stir bar and stopper. The flaskwas heated to 40° C. to form a solution. The solution was then polishfiltered and transferred to a reactor at 40° C. with agitator, nitrogenline, thermocouple and cooling water, using 122.81 g of isopropanol torinse the flask and polish filter. 603.2 g of heptane was added and thesolution was agitated. The reactor was cooled to a jacket temperature of35° C. and 6.91 g of isopropanol was added to the reactor drop wise tocreate a clear solution. The solution was agitated and then seeded with972 mg ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(Form A) and then agitated. The reactor was then cooled to 20° C. andthen agitated. 1889.24 g of heptane was added using an external pump.Following agitation, the slurry was filtered, washed with 15:85 wt/wtisopropanol:heptane and dried. 531.7 g ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof crystal Form A, having greater than 97% chiral purity, and greaterthan 99% chemical purity, was obtained, representing a yield of about88%.

An NMR spectrum of theR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideobtained in Example 8 is illustrated in FIG. 9, having the followingcharacteristics: ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.12 (t, J=7.24Hz, 3H) 1.26 (t, J=7.43 Hz, 3H) 1.56-1.76 (m, 3H) 1.84-1.94 (m, 1H)2.15-2.29 (m, 2H) 2.59-2.66 (m, 1H) 2.81-2.90 (m, 1H) 3.08-3.29 (m, 4H)3.70 (ddd, J=13.69, 7.24, 2.93 Hz, 1H) 3.94 (s, 3H) 5.53 (s, 2H) 6.22(s, 1H) 8.06 (br d, J=4.70 Hz, 1H) 8.53 (s, 1H).

Referring to FIGS. 7A-7C, FIGS. 7A-7C present data on theR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide,(R)-amisulpride, of crystal Form A obtained in Example 8. FIG. 7A is aDSC thermogram for crystal Form A of (R)-amisulpride obtained in Example8; FIG. 7B a XRPD pattern for crystal Form A of (R)-amisulpride obtainedin Example 8; and FIG. 7C a micrograph image crystals of crystal Form Aof the (R)-amisulpride obtained in Example 7.

Example 9: Synthesis ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude freebase)

153 g of 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid and 789 g ofacetone were placed in a flask fitted with a stir bar, a thermocoupleand a nitrogen line. The solution was cooled to −8° C., and then 70.4 gof ethyl chloroformate was added to the flask. An addition funnel wasfitted to the flask and 79.3 g of 4-methyl morpholine was added dropwise, maintaining the temperature below 0° C. The mixture was agitatedat −8° C. and then 55 g of (S)-(1-ethylpyrrolidin-2-yl)methanamine wasadded drop wise. The mixture was agitated at 0° C. for 1 hour, warmed toambient temperature and then further agitated at ambient temperature toprovideS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidestarting material. The reaction was then concentrated to minimum volumeand 822 g of water, followed by 311 g of ethyl acetate, was added. Themixture was agitated and the organic layer removed. The solution washeated to 35° C. and 755 g of ethyl acetate and 326 g of 40 wt %potassium carbonate (aq) were added. The mixture was agitated, thephases allowed to separate, and the aqueous layer removed. Then 296 g ofwater of water was added, the mixture agitated, the phases allowed toseparate and the aqueous layer removed. 302 g of water was added, themixture agitated, the phases allowed to separate and the aqueous layerremoved. The organic layer was transferred to a flask with a mechanicalstirrer, a thermocouple and a nitrogen line. The organic layer wasconcentrated to dryness and 531 g of ethyl acetate was added. Afteragitation, the solution was concentrated to 400 mL. Then 305 g of ethylacetate was added and the solution was concentrated to 400 mL and was0.35 wt % water by Karl Fischer titration. The solution was then cooledto 30° C. and seeded with 300 mg ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideand a slurry formed. The solution was then cooled to 20° C. andagitated, and 495 g of methyl t-butyl ether was added. The slurry wasthen filtered, washed with 3:1 wt/wt methyl t-butyl ether:ethyl acetateand dried. 160.7 g ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidewas obtained as a crystalline solid, representing a yield of about 74%.

Example 10: Recrystallization of:S-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(freebase crystal Form A′)

300.19 g ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(prepared substantially according to Example 9) and 240.2 g ofisopropanol were added to a flask with a stir bar and stopper. The flaskwas heated to 40° C. to form a solution. The solution was then polishfiltered and transferred to a reactor at 40° C. with agitator, nitrogenline, thermocouple and cooling water, using 59.8 g of isopropanol torinse the flask and polish filter. 300.4 g of heptane was added and thesolution agitated. The reactor was cooled to a jacket temperature of 35°C. and 6.91 g of isopropanol was added to the reactor drop wise tocreate a clear solution. The solution was agitated and then seeded with602 mg ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(Form A′) and then agitated. The reactor was then cooled to 20° C. andagitated. 1399.86 g of heptane was added using an external pump.Following agitation, the slurry was filtered, washed with 15:85isopropanol:heptane and dried. 281.03 g ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof crystal Form A′ having greater than 97% chiral purity, and greaterthan 98% chemical purity, was obtained, representing a yield of about91%.

An NMR spectrum of theS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideobtained in Example 10 is illustrated in FIG. 10, having the followingcharacteristics: ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.12-1.23 (m, 6H)1.57-1.66 (m, 1H) 1.68-1.80 (m, 2H) 1.95 (dq, J=12.18, 8.33 Hz, 1H)2.20-2.36 (m, 2H) 2.68 (dtd, J=8.61, 6.26, 6.26, 3.91 Hz, 1H) 2.91 (dq,J=12.08, 7.32 Hz, 1H) 3.12-3.27 (m, 3H) 3.32-3.48 (m, 1H) 3.60 (dd,J=13.30, 3.91 Hz, 1H) 3.97 (s, 3H) 6.49 (s, 1H) 8.28 (s, 1H).

Referring to FIGS. 8A-8C, FIGS. 8A-8C present data on theS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide,(S)-amisulpride, of crystal Form A′ obtained in Example 10. FIG. 8A is aDSC thermogram for crystal Form A′ of(S)-amisulpride obtained in Example10; FIG. 8B a XRPD pattern for crystal Form A′ of (S)-amisulprideobtained in Example 10; and FIG. 8C a micrograph image showing crystalsof crystal Form A′ of the (S)-amisulpride obtained in Example 10.

Example 11: General Overview of Preparation ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide

In overview,R-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A can be prepared in two steps: Step 1 Preparation of Crude(R)-amisulpride; and Step 2 Recrystallization of the Crude(R)-amisulpride to crystalline (R)-amisulpride of Form A.

Step 1, Examples 11 and 12

Step 1 in general comprises mixing4-Amino-5-(ethylsulfonyl)-2-methoxybenzoic acid with ethyl chloroformateand then reacting with (R)-(1-ethyl pyrrolidin-2-yl)methanamine to formR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidehydrochloride. Other coupling reagents such as methyl, isopropyl andisobutyl chloroformates and dimethoxytriazinechloride are also suitablefor carrying out the coupling reaction. The resulting product isextracted into water and washed with ethyl acetate. TheR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidehydrochloride is converted to freebase, dissolved into ethyl acetate andwashed with base and water. The ethyl acetate solution is then dried andconcentrated. The ethyl acetate solvate ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidecrystallizes and is converted toR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude freebase) by the addition of methyl-tert butyl ether. TheR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude freebase) is then isolated by filtration.

Step 2, Examples 11 and 12

Step 2 in general comprises dissolving theR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude freebase) of Step 1 into isopropanol and polish filtering. Theisopropanol solution is concentrated, diluted with n-heptane and seededwith Form A to yieldR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-ethylsulfonyl)-2-methoxybenzamidefreebase crystals. The mixture is then cooled and filtered to yieldcrystallineR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidesubstantially of Form A.

It is to be understood that during the crystallization ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude freebase) the amount of water in the ethyl acetate solventaffects the crystallization and is preferably less than 0.5%.Accordingly the water content is preferably monitored during thedistillation of the ethyl acetate solution, such as for example bycoulometric titration (Karl Fischer). For example, in variousembodiments coulometric titration (Karl Fischer) was performed bynon-aqueous, perchloric acid titration where approximately 300 mg ofsample, accurately weighed, was dissolved in about 50 mL of glacialacetic acid and titrated with 0.1 N perchloric acid and the end-pointdetermined potentiometrically. The weight of sample was corrected forwater content and residual solvent content prior to assay calculation.The drying of the isolated solid is also preferably monitored. Invarious embodiments, the reaction of Step 1 is considered complete whenthe amount of 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid in thereaction mixture is less than or equal to 10 A % (where A % refers toArea % by HPLC) and/or when the amount of4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid in the reaction mixtureis less than or equal to 10 mol %.

Example 12: Detailed Overview of Preparation ofR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A

Step 1: To a mixture of 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acidin acetone at −10° C. and ethyl chloroformate, 4-methylmorpholine isadded at a rate (exothermic) so as to maintain the internal temperaturebelow −5° C. The reaction is stirred for 1 hour at −10° C. and then(R)-(1-ethyl pyrrolidin-2-yl)methanamine is added. After stirring for 2hours the reaction mixture is concentrated and diluted with water andethyl acetate. The ethyl acetate layer is removed and the aqueous layeris basified with potassium carbonate. Ethyl acetate is added and theaqueous layer removed. The organic layer is washed with water twice andconcentrated. The mixture is diluted with ethyl acetate and concentrateduntil water content of the ethyl acetate solution is below 0.5%. Thesolution is seeded at 31° C. with 1 wt % Form A and stirred at thenucleation temperature for 2 h. The mixture is cooled to 20° C. andstirred for 1 h. The slurry is diluted with methyl tert butylether(MtBE) and stirred for 2 h at 20 C. The suspension is filtered and theproduct cake is washed with MtBE/ethyl acetate. The wet-cake is driedunder vacuum at 40° C.±5° C. to constant weight to yieldR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude).

Step 2: Isopropanol andR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude) are mixed together. The mixture is heated to 50° C. to achievedissolution and then passed through a filter. The filtrate isconcentrated and cooled to 40° C. n-Heptane is added and the resultingsolution is cooled to 28° C. and seeded with Form A. The resultingslurry is cooled to 23° C. and stirred for 1.5 h at this temperature.More n-heptane is added and the slurry is stirred at 22° C. for 13 h.The suspension is filtered and the product cake is washed withisopropanol/N-heptane. The wet-cake is dried under vacuum at 40° C.±5°C. to constant weight to yieldR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A.

An NMR spectrum of theR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A obtained by the methods of Examples 11 and 12 is illustratedin FIG. 11A, and FIG. 11B provides the number scheme used for theassignments of Table 13 based on the NMR spectrum of FIG. 11A, where thefollowing notation is used in Table 13: s: singlet, d: doublet, br s:broad singlet, br d broad doublet, ddd: doublet of doublets of doublets,t: triplet, q: quadruplet; m: multiplet, tt: triplet of triplets; dq:doublet of quadruplets.

TABLE 13 Assignment of ¹H NMR Spectrum of FIG. 11A Carbon Chemical (seeFIG. 11B) Shift Details  1 1.19-1.20 t, J = 7.54 Hz, 3 H  2 3.02-3.08 q,J = 7.43 Hz, 2 H  5 6.28 s, 1 H  8 8.45 s, 1 H 10a,b 3.18-3.23 ddd, J =13.50, 4.89, 2.74 Hz, 1 H 3.60-3.66 ddd, J = 13.69, 7.04, 2.74 Hz, 1 H11 2.53-2.64 m, 1 H 12a,b 1.52-1.59 m, 1 H 1.79-1.85 m, 1 H 13 1.64-1.69m, 2 H 14a,b 2.09-2.15 m, 1 H 3.12-3.17 m, 1 H 15a,b 2.18-2.21 m, 1 H2.74-2.81 dq, J = 11.93, 7.37 Hz, 1 H 16 1.04-1.06 t, J = 7.04 Hz, 3 H17 3.88 s, 3 H 18 5.71 s, 2 H 19 8.05-8.07 br dd, J = 7.04, 2.35 Hz, 1 H

A ¹³C NMR spectrum of theR-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A obtained by the methods of Examples 11 and 12 is illustratedin FIG. 12A, and FIG. 12B provides the number scheme used for theassignments of Table 14 based on the ¹³C NMR spectrum of FIG. 12A.

TABLE 14 Assignment of ¹³C NMR Spectrum of FIG. 12A Chemical ShiftAssignment (ppm) (see FIG. 12B) 7.15 1 49.45 2 112.24 3 111.83 4 98.53 5162.44 6 150.84 7 136.04 8 164.17 9 41.29 10 62.14 11 28.39 12 22.82 1353.54 14 47.82 15 14.14 16 56.03 17

Example 13: General Overview of Preparation ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide

In overview,S-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A′ can be prepared in two steps: Step 1 Preparation of Crude(S)-amisulpride; and Step 2 Recrystallization of the Crude(S)-amisulpride to crystalline (S)-amisulpride of Form A′.

Step 1, Examples 13 and 14

Step 1 in general comprises reacting4-Amino-5-(ethylsulfonyl)-2-methoxybenzoic acid with ethyl chloroformateand then adding (S)-(1-ethyl pyrrolidin-2-yl)methanamine to formS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide hydrochloride. The resulting product isextracted into water and washed with ethyl acetate.S-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidehydrochloride is converted to freebase by the addition of aqueouspotassium carbonate, dissolved into ethyl acetate and washed with water.The ethyl acetate solution is dried and concentrated. The ethyl acetatesolvate ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidecrystallizes and is desolvated by the addition of methyl-tert butylether. TheS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude freebase) is isolated by filtration.

Step 2, Examples 13 and 14

Step 2 in general comprises dissolving theS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude freebase) of into isopropanol and polish filtering. Theisopropanol solution is concentrated, diluted with n-heptane and seededwith Form A′ to yield a slurry ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide.The mixture is cooled and filtered to yield crystallineS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide substantially of Form A′.

It is to be understood that during the crystallization ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude freebase) the amount of water in the ethyl acetate solventaffects the crystallization and is preferably less than 0.5%.Accordingly the water content is preferably monitored during thedistillation of the ethyl acetate solution, such as for example bycoulometric titration (Karl Fischer). For example, in variousembodiments coulometric titration (Karl Fischer) was performed bynon-aqueous, perchloric acid titration where approximately 300 mg ofsample, accurately weighed, was dissolved in about 50 mL of glacialacetic acid and titrated with 0.1 N perchloric acid and the end-pointdetermined potentiometrically. The weight of sample was corrected forwater content and residual solvent content prior to assay calculation.The drying of the isolated solid is also preferably monitored. Invarious embodiments, the reaction of Step 1 is considered complete whenthe amount of 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid in thereaction mixture is less than or equal to 10 A % (where A % refers toArea % by HPLC) and/or when the amount of4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid in the reaction mixtureis less than or equal to 10 mol %.

Example 14: Detailed Overview of Preparation ofS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A′

Step 1: To a solution of 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acidin acetone at −10° C. is added ethyl chloroformate. 4-Methylmorpholineis added at a rate (exothermic) so as to maintain the internaltemperature below −5° C. The reaction is stirred for 1 hour at −10° C.and then (S)-(1-ethyl pyrrolidin-2-yl)methanamine is added. Afterstirring for 2 hours the reaction mixture is concentrated and dilutedwith water and ethyl acetate. The ethyl acetate layer is removed and theaqueous layer is basified with potassium carbonate. Ethyl acetate isthen added and the aqueous layer removed. The organic layer is washedwith water twice and concentrated. The mixture is diluted with ethylacetate and concentrated until the water content of the ethyl acetatesolution is below 0.5%. The solution is seeded at 31° C. with 1 wt %S-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A′ and stirred at the nucleation temperature for 2 h. Themixture is cooled to 20° C. and stirred for 1 h. The slurry is thendiluted with methyl tert butylether (MtBE) and stirred for 2 h at 20° C.The suspension is then filtered and the product cake is washed withMtBE/ethyl acetate. The wet-cake is dried under vacuum at 40° C.±5° C.to constant weight to yieldS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude).

Step 2: Isopropanol is added toS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide(crude) and the mixture is heated to 50° C. to achieve dissolution. Theresulting solution is then passed through a filter. The filtrate isconcentrated and cooled to 40° C. n-Heptane is then added and theresulting solution is cooled to 28° C. and seeded. The resulting slurryis cooled to 23° C. and stirred for 1.5 h at this temperature. Moren-heptane is added and the slurry is stirred at 22° C. for 13 h. Thesuspension is then filtered and the product cake is washed withisopropanol/n-heptane. The wet-cake is dried under vacuum at 40° C.±5°C. to constant weight to yieldS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamidesubstantially of Form A′.

An NMR spectrum of theS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A′ obtained by the methods of Examples 13 and 14 is illustratedin FIG. 13A, and FIG. 13B provides the number scheme used for theassignments of Table 15 based on the NMR spectrum of FIG. 13A, where thefollowing notation is used in Table 15: s: singlet, d: doublet, br s:broad singlet, br d broad doublet, ddd: doublet of doublets of doublets,t: triplet, q: quadruplet; m: multiplet, tt: triplet of triplets; dq:doublet of quadruplets.

TABLE 15 Assignment of ¹H NMR Spectrum of FIG. 13A Carbon Chemical (seeFIG. 13B) Shift Details  1 1.21-1.25 t, J = 7.43 Hz, 3 H  2 3.05-3.11 q,J = 7.30 Hz, 2 H  5 6.20 s, 1 H  8 8.50 s, 1 H 10a,b 3.22-3.26 ddd, J =13.69, 4.89, 2.93 Hz, 1 H 3.64-3.70 ddd, J = 13.69, 7.04, 2.74 Hz, 1 H11 2.57-2.61 m, 1 H 12a,b 1.57-1.64 m, 1 H 1.83-1.88 m, 1 H 13 1.66-1.72m, 2 H 14a,b 2.12-2.16 m, 1 H 3.13-3.18 m, 1 H 15a,b 2.19-2.23 m, 1 H2.79-2.84 dq, J = 12.13, 7.43 Hz, 1 H 16 1.07-1.11 t, J = 7.24 Hz, 3 H17 3.91 s, 3 H 18 5.51 br s, 2 H 19 8.02-8.03 br d, J = 5.1 Hz, 1 H

A ¹³C NMR spectrum of theS-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamideof Form A′ obtained by the methods of Examples 13 and 14 is illustratedin FIG. 14A, and FIG. 14B provides the number scheme used for theassignments of Table 16 based on the ¹³C NMR spectrum of FIG. 14A.

TABLE 16 Assignment of ¹³C NMR Spectrum of FIG. 14A Chemical ShiftAssignment (ppm) (see FIG. 14 B) 7.23 1 49.67 2 112.81 3 112.30 4 98.445 162.41 6 150.54 7 136.35 8 164.05 9 41.31 10 62.23 11 28.43 12 22.9013 53.63 14 47.89 15 14.23 16 56.00 17

Although the invention has been described with reference to a specificembodiment this description is not meant to be construed in a limitingsense. The invention being thus described, it is apparent that the samecan be varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the present invention, and allsuch modifications, alternatives, and equivalents as would be obvious toone skilled in the art are intended to be included within the scope ofthe following claims.

What is claimed is:
 1. A method of alleviating bipolar disordercomprising administering to a subject in need thereof an effectiveamount of a composition comprising: an amount about 85 mg to about 600mg of (R)-(+)-amisulpride, or a pharmaceutically acceptable saltthereof, by weight of free base; and an amount about 15 mg to about 100mg (S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof,by weight of free base; wherein the enantiomeric ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride in the composition is about65:35 to about 88:12 by weight of free base.
 2. The method of claim 1wherein the enantiomeric ratio of (R)-(+)-amisulpride to(S)-(−)-amisulpride is about 75:25 to about 88:12 by weight of freebase.
 3. The method of claim 1 wherein the enantiomeric ratio of(R)-(+)-amisulpride to (S)-(−)-amisulpride is about 80:20 to about 88:12by weight of free base.
 4. The method of claim 1 wherein theenantiomeric ratio of (R)-(+)-amisulpride to (S)-(−)-amisulpride isabout 85:15 by weight of free base.
 5. The method of claim 1 wherein thecomposition comprising: an amount about 170 mg to about 340 mg of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, byweight of free base; and an amount about 30 mg to about 60 mg(S)-(−)-amisulpride, or a pharmaceutically acceptable salt thereof, byweight of free base.
 6. The method of claim 1 wherein the compositioncomprising: an amount about 170 mg of (R)-(+)-amisulpride, or apharmaceutically acceptable salt thereof, by weight of free base; and anamount about 30 mg of (S)-(−)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base.
 7. The method of claim1 wherein the composition comprising: an amount about 340 mg of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, byweight of free base; and an amount about 60 mg of (S)-(−)-amisulpride,or a pharmaceutically acceptable salt thereof, by weight of free base.8. The method of claim 1 wherein the composition comprising a combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, is about 100 mg, about 200mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg or about 700mg by weight of free base.
 9. The method of claim 1 wherein thecomposition comprising a combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, isabout 200 mg to about 600 mg by weight of free base.
 10. The method ofclaim 1 wherein the composition comprising a combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, is about 200 mg to about 400 mg by weight offree base.
 11. The method of claim 1 wherein the composition comprisinga combined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, is about 200 mg by weight offree base.
 12. The method of claim 1 wherein the composition comprisinga combined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, is about 400 mg by weight offree base.
 13. The method of claim 1 wherein the bipolar disorder isbipolar depression.
 14. The method of claim 1 wherein the(R)-(+)-amisulpride is crystalline (R)-(+)-amisulpride of crystal FormA; and the (S)-(−)-amisulpride is crystalline (S)-(−)-amisulpride ofcrystal Form A′; wherein Form A is characterized by a powder x-raydiffraction pattern comprising peaks, in terms of 2-theta, at 7.0±0.2°,9.7±0.2°, and 15.4±0.2°; and Form A′ is characterized by a powder x-raydiffraction pattern comprising peaks, in terms of 2-theta, at 7.0±0.2°,9.7±0.2°, and 15.4±0.2°.
 15. The method of claim 1 wherein thecomposition comprising a combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, iseffective to provide in the subject after administration an occupancy ofdopamine D2 receptors about 20% to about 60%.
 16. The method of claim 1wherein the composition comprising a combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, is effective to provide in the subject afteradministration an occupancy of dopamine D2 receptors about 30% to about50%.
 17. The method of claim 1 wherein the composition comprising acombined amount of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, is effective to provide inthe subject after administration a suppression of the time in rapid eyemovement (REM) sleep as characterized by a decrease in REM sleep by anamount greater than 10 minutes.
 18. The method of claim 1 wherein thecomposition comprising a combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, iseffective to provide in the subject after administration a suppressionof the time in rapid eye movement (REM) sleep as characterized by adecrease in REM sleep by an amount about 15 minutes to about 45 minutes.19. The method of claim 1 wherein the composition comprising a combinedamount of (R)-(+)-amisulpride and (S)-(−)-amisulpride, orpharmaceutically acceptable salts thereof, is effective to provide inthe subject after administration a suppression of the time in rapid eyemovement (REM) sleep as characterized by a decrease in REM sleep by anamount about 15 minutes to about 30 minutes.
 20. The method of claim 1wherein the composition comprising a combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, is effective to provide in the subject afteradministration a suppression of the time in rapid eye movement (REM)sleep as characterized by a latency to REM sleep by an amount greaterthan 20 minutes.
 21. The method of claim 1 wherein the compositioncomprising a combined amount of (R)-(+)-amisulpride and(S)-(−)-amisulpride, or pharmaceutically acceptable salts thereof, iseffective to provide in the subject after administration a suppressionof the time in rapid eye movement (REM) sleep as characterized by alatency to REM sleep by an amount greater than 30 minutes.
 22. Themethod of claim 1 wherein the composition comprising a combined amountof (R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, is effective to provide in the subject afteradministration a suppression of the time in rapid eye movement (REM)sleep as characterized by a decrease in total REM sleep time relative tototal sleep time by an amount greater than 5%.
 23. The method of claim 1wherein the composition comprising a combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, is effective to provide in the subject afteradministration a suppression of the time in rapid eye movement (REM)sleep as characterized by a decrease in total REM sleep time relative tototal sleep time by an amount greater than 6.5%.
 24. The method of claim1 wherein the composition comprising a combined amount of(R)-(+)-amisulpride and (S)-(−)-amisulpride, or pharmaceuticallyacceptable salts thereof, is effective to provide in the subject afteradministration: an occupancy of dopamine D2 receptors about 30% to about50%; and a suppression of the time in rapid eye movement (REM) sleep byan amount about 15 minutes to about 45 minutes.
 25. The method of claim1 wherein the composition is administered once daily.
 26. A method ofalleviating bipolar depression comprising administering once daily to asubject in need thereof an effective amount of a composition comprising:an amount about 170 mg of (R)-(+)-amisulpride, or a pharmaceuticallyacceptable salt thereof, by weight of free base; and an amount about 30mg of (S)-(−)-amisulpride, or a pharmaceutically acceptable saltthereof, by weight of free base.
 27. The method of claim 26 wherein the(R)-(+)-amisulpride is crystalline (R)-(+)-amisulpride of crystal FormA; and the (S)-(−)-amisulpride is crystalline (S)-(−)-amisulpride ofcrystal Form A′; wherein Form A is characterized by a powder x-raydiffraction pattern comprising peaks, in terms of 2-theta, at 7.0±0.2°,9.7±0.2°, and 15.4±0.2°; and Form A′ is characterized by a powder x-raydiffraction pattern comprising peaks, in terms of 2-theta, at 7.0±0.2°,9.7±0.2°, and 15.4±0.2°.
 28. A method of alleviating bipolar depressioncomprising administering once daily to a subject in need thereof aneffective amount of a composition comprising: an amount about 340 mg of(R)-(+)-amisulpride, or a pharmaceutically acceptable salt thereof, byweight of free base; and an amount about 60 mg of (S)-(−)-amisulpride,or a pharmaceutically acceptable salt thereof, by weight of free base.29. The method of claim 28 wherein the (R)-(+)-amisulpride iscrystalline (R)-(+)-amisulpride of crystal Form A; and the(S)-(−)-amisulpride is crystalline (S)-(−)-amisulpride of crystal FormA′; wherein Form A is characterized by a powder x-ray diffractionpattern comprising peaks, in terms of 2-theta, at 7.0±0.2°, 9.7±0.2°,and 15.4±0.2°; and Form A′ is characterized by a powder x-raydiffraction pattern comprising peaks, in terms of 2-theta, at 7.0±0.2°,9.7±0.2°, and 15.4±0.2°.